Pyrrolopyridazine compounds

ABSTRACT

A pyrrolopyridazine compound having the formula (I) or a pharmaceutically acceptable salt thereof:                    
     wherein, R 1  is a C 2 -C 6  alkenyl group, a halogeno C 2 -C 6  alkenyl group, a C 3 -C 7  cycloalkyl group which may be optionally substituted or a C 3 -C 7  cycloalkyl- C 1 -C 6  alkyl group which may be optionally substituted. R 2  is a C 1 -C 6  alkyl group. R 3  is a hydroxymethyl group, a C 2 -C 6  aliphatic acyloxymethyl group, a C 6 -C 10  arylcarbonyloxymethyl group which may be optionally substituted, a C 1 -C 6  alkoxycarbonyloxymethyl group, a formyl group, a carboxyl group, a C 1 -C 6  alkoxycarbonyl group or a C 6 -C 10  aryloxycarbonyl group which may be optionally substituted. R 4  is a C 6 -C 10  aryl group which may be optionally substituted. A is an imino group, an oxygen atom or a sulfur atom. These compounds exhibit excellent gastric acid secretory inhibition activity and gastric mucous membrane protection activity etc. They are useful for prevention or treatment of ulcerative diseases and for  Helicobacter pylori  infections.

This is a continuation application of international applicationPCT/JP01/00820 filed Feb. 6, 2001.

TECHNICAL FIELD

This invention relates to pyrrolopyridazine derivatives orpharmaceutically acceptable salts thereof; to pharmaceuticalcompositions comprising a pyrrolopyridazine derivative or apharmaceutically acceptable salt thereof (preferably compositions forthe prevention or treatment of ulcerative disease) as an activeingredient; to the use of a pyrrolopyridazine derivative or apharmaceutically acceptable salt thereof in the preparation of apharmaceutical composition (preferably a composition for the preventionor treatment of ulcerative disease); or to a method for the preventionor treatment of disease (preferably ulcerative disease), which methodcomprises administering a pharmaceutically effective amount of apyrrolopyridazine derivative or a pharmaceutically acceptable saltthereof to a warm-blooded animal (preferably a human).

BACKGROUND OF THE INVENTION

It has been considered that an inbalance between aggressive factors andprotective factors against the gastric mucous membrane induces pepticulcers. Gastric acid secretion is an aggressive factor and suppressionof gastric acid secretion is useful in the prevention and treatment ofthe disease. Anticholinergic agents, histamine H₂ receptor antagonistssuch as cimetidine and the like and proton pump inhibitors such asomeprazole and the like have been clinically used as a gastric acidsecretion inhibitor. Although these agents are excellent therapeuticagents for ulcerative disease, the disease may recur after cessation ofthe therapy. It has been recently reported that Helicobacter pylonrelates to recurrence of the ulcerative disease. Actually there havebeen some attempts to use a gastric acid secretion inhibitor incombination with an antibacterial agent for treatment of the disease.

Accordingly a compound that exhibits potent gastric acid secretoryinhibition activity, excellent gastric mucous membrane protectionactivity and potent antibacterial activity against Helicobacter pyloriwould be expected to be an excellent medicament (preferably aprophylactic and therapeutic agent for ulcerative disease).

Some pyrrolopyridazine derivatives that have gastric acid secretoryinhibition activity and gastric mucous membrane protection activity havebeen known (for example, WO 91/17164, WO 92/06979, WO 93/08190 and thelike). The activity against Helicobacter pylori of somepyrrolopyridazine derivatives has also been known (for example, JapanesePatent Application Publication Hei 7-247285 and the like).

DISCLOSURE OF THE INVENTION

The inventors have continued an investigation on the pharmacologicalactivities of pyrrolopyridazine derivatives in order to discover amedicament (preferably an agent for ulcerative disease) that exhibitspotent gastric acid secretory inhibition activity, protects gastricmucous membranes and has excellent antibacterial activity againstHelicobacter pylori for a long time. As a result, they found that somepyrrolopyridazine derivatives substituted with specific substituents atthe 3-position exhibit potent gastric acid secretory inhibition activityand gastric mucous membrane protection activity and exhibit excellentantibacterial activity against Helicobacter pylori.

The pyrrolopyridazine derivative, i.e., compound, of the presentinvention has the following formula:

wherein:

R¹ represents a C₂-C₆ alkenyl group, a halogeno C₂-C₆ alkenyl group, aC₃-C₇ cycloalkyl group which may be optionally substituted with C₁-C₆alkyl or a C₃-C₇ cycloalkyl-C₁-C₆ alkyl group which may be optionallysubstituted with C₁-C₆ alkyl; R² represents a C₁-C₆ alkyl group;

R³ represents a hydroxymethyl group, a C₂-C₆ aliphatic acyloxymethylgroup, a C₆-C₁₀ arylcarbonyloxymethyl group which may be optionallysubstituted with substituents selected from the group consisting ofC₁-C₆ alkyl, C₁-C₆ alkoxy and halogeno, a C₁-C₆ alkoxycarbonyloxymethylgroup, a formyl group, a carboxyl group, a C₁-C₆ alkoxycarbonyl group ora C₆-C₁₀ aryloxycarbonyl group which may be optionally substituted withsubstituents selected from the group consisting of C₁-C₆ alkyl, C₁-C₆alkoxy and halogeno;

R⁴ represents a C₆-C₁₀ aryl group which may be optionally substitutedwith substituents selected from the group consisting of C₁-C₆ alkyl,halogeno C₁-C₆ alkyl, C₁-C₆ alkoxy, halogeno C₁-C₆ alkoxy and halogeno;

A represents an imino group, an oxygen atom or a sulfur atom;

In the formula (I) described above:

The C₁-C₆ alkyl group in the definition of R² or the C₁-C₆ alkyl moietyincluded in the definition of R¹, R³ or R⁴ is, for example, a methyl,ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl t-butyl, pentyl orhexyl group; preferably a C₁-C₄ alkyl group; more preferably a methyl orethyl group; and most preferably a methyl group.

The C₂-C₆ alkenyl group or C₂-C₆ alkenyl moiety of the halogeno C₂-C₆alkenyl group in the definition of R¹ is, for example, a vinyl,1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl,1-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-1-propenyl,2-methyl-2-propenyl, 2-pentenyl or 2-hexenyl group; preferably a C₂-C₄alkenyl group, more preferably a C₃-C₄ alkenyl group; still morepreferably a 2-propenyl or 2-butenyl group; and most preferably a2-butenyl group.

A typical example of a halogeno C₂-C₆ alkenyl group in the definition ofR¹ is, for example, a 2,2-difluorovinyl, 3-fluoro-2-propenyl,3-chloro-2-propenyl, 3-bromo-2-propenyl, 3-iodo-2-propenyl,3,3-difluoro-2-propenyl, 2,3-dichloro-2-propenyl,3,3-dichloro-2-propenyl, 2,3-dibromo-2-propenyl, 3,3-dibromo-2-propenyl,4,4,4-trifluoro-2-butenyl, 5-fluoro-2-pentenyl or 6-fluoro-2-hexenylgroup; preferably a 3-chloro-2-propenyl, 3,3-difluoro-2-propenyl,3,3-dichloro-2-propenyl or 4,4,4-trifluoro-2-butenyl group; and morepreferably a 3-chloro-2-propenyl, 3,3-difluoro-2-propenyl or3,3-dichloro-2-propenyl group.

The C₃-C₇ cycloalkyl moiety of the C₃-C₇ cycloalkyl group which may beoptionally substituted with a C₁-C₆ alkyl group or of the C₃-C₇cycloalkyl-C₁-C₆ alkyl group which may be optionally substituted with aC₁-C₆ alkyl group in the definition of R¹ is, for example, acyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group;preferably a C₃-C₆ cycloalkyl group; more preferably a cyclopropyl,cyclopentyl or cyclohexyl group; and most preferably a cyclopropylgroup.

A typical example of the C₃-C₇ cycloalkyl group which may be optionallysubstituted with a C₁-C₆ alkyl group in the definition of R¹ is, forexample, a cyclopropyl, 2-ethylcyclopropyl, 2-thylcyclopropyl,2-ropylcyclopropyl, 2-exylcyclopropyl, cyclobutyl, 2-methylcyclobutyl,cyclopentyl, 2-methylcyclopentyl, 2-ethylcyclopentyl, cyclohexyl,2-methylcyclohexyl or cycloheptyl group; preferably a cyclopropyl,2-methylcyclopropyl, 2-ethylcyclopropyl, cyclobutyl, cyclopentyl,2-methylcyclopentyl, cyclohexyl or 2-methylcyclohexyl group; morepreferably a cyclopropyl, 2-methylcyclopropyl, cyclopentyl,2-methylcyclopentyl, cyclohexy or 2-methylcyclohexyl group; and mostpreferably a cyclopropyl or 2-methylcyclopropyl group.

A typical example of the C₃-C₇ cycloalkyl-C₁-C-₆ alkyl group which maybe optionally substituted with a C₁-C₆ alkyl group in the definition ofR¹ is, for example, a cyclopropylmethyl, 2-cyclopropylethyl,2-methylcyclopropylmethyl, 2-(2-methylcyclopropyl)ethyl,3-(2-methylcyclopropyl)propyl, 6-(2-methylcyclopropyl)hexyl,2-ethylcyclopropylmethyl, 2-propylcyclopropylmethyl,2-hexylcyclopropylmethyl, cyclobutylmethyl, 2-methylcyclobutylmethyl,cyclopentylmethyl, 2-cyclopentylethyl, 2-methylcyclopentylmethyl,2-(2-methylcyclopentyl)ethyl, 2-ethylcyclopentylmethyl,cyclohexylmethyl, 2-cyclohexylethyl, 2-methylcyclohexylmethyl,2-(2-methylcyclohexyl)ethyl or cycloheptylmethyl group; preferably acyclopropylmethyl, 2-cyclopropylethyl, 2-methylcyclopropylmethyl,2-(2-methylcyclopropyl)ethyl, 2-ethylcyclopropylmethyl,cyclobutylmethyl, 2-methylcyclobutylmethyl, cyclopentylmethyl,2-methylcyclopentylmethyl, cyclohexylmethyl or 2-methylcyclohexylmethylgroup; more preferably a cyclopropylmethyl, 2-methylcyclopropylmethyl,2-ethylcyclopropylmethyl, cyclobutylmethyl, 2-methylcyclobutylmethyl,cyclopentylmethyl or 2-methylcyclohexylmethyl group; more preferably acyclopropylmethyl, 2-methylcyclopropylmethyl, cyclopentylmethyl or2-methylcyclohexylmethyl group; still more preferably acyclopropylmethyl or 2-methylcyclopropylmethyl group; and mostpreferably a 2-methylcyclopropylmethyl group.

The C₂-C₆ aliphatic acyl moiety of the C₂-C₆ aliphatic acyloxymethylgroup in the definition of R³ is, for example, an acetyl, propionyl,butyryl, isobutyryl, valeryl, isovaleryl or hexanoyl group; preferably aC₂-C₄ aliphatic acyl group; more preferably a C₂-C₃ aliphatic acylgroup; and most preferably an acetyl group.

The C₁-C₆ alkoxy moiety of a substituent of the aryl group or a C₁-C₆alkoxy moiety of the halogeno C₁-C₆ alkoxy group of a substituent of thearyl group in the definition of R³ and R⁴ or the C₁-C₆ alkoxy moiety ofthe C₁-C₆ alkoxycarbonyloxymethyl group and the C₁-C₆ alkoxycarbonylgroup in the definition of R³ is, for example, a methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy orhexyloxy group; preferably a C₁-C₄ alkoxy group; more preferably amethoxy or ethoxy group; and most preferably a methoxy group.

The halogen atom included in the definition of R¹, R³ and R⁴ is, forexample, a fluorine, chlorine, bromine or iodine atom; preferably afluorine, chlorine or bromine atom; more preferably a fluorine orchlorine atom.

The C₆-C₁₀ aryl moiety of the optionally substituted C₆-C₁₀ aryl moietyin the definition of R³ or of the optionally substituted C₆-C₁₀ arylgroup in the definition of R⁴ is, for example, a phenyl or naphthylgroup; preferably a phenyl group.

The number of the substitutents on the aryl group is, for example from 1to 5; preferably from 1 to 3; more preferably 1 or 2; and mostpreferably one.

The preferred C₆-C₁₀ aryl moiety which may be optionally substitutedwith substituents selected from the group consisting of C₁-C₆ alkyl,C₁-C₆ alkoxy and halogeno in the definition of R³ is, for example, aphenyl, methylphenyl, dimethylphenyl, methoxyphenyl, dimethoxyphenyl,fluorophenyl, chlorophenyl, bromophenyl, difluorophenyl,chlorofluorophenyl, dichlorophenyl, naphthyl, methylnaphtyl,methoxynaphthyl, fluoronaphthyl, chloronaphthyl or bromonaphthyl group;more preferably a phenyl, methylphenyl, methoxyphenyl, fluorophenyl orchlorophenyl group; most preferably a phenyl or methylphenyl group.

The preferred C₆-C₁₀ aryl group which may be optionally substituted withsubstituents selected from the group consisting of C₁-C₆ alkyl, halogenoC₁-C₆ alkyl, C₁-C₆ alkoxy, halogeno C₁-C₆ alkoxy, and halogeno in thedefinition of R⁴ is, for example, a phenyl, methylphenyl,trifluoromethylphenyl, methoxyphenyl, trifluoromethoxyphenyl,difluoromethoxyphenyl, fluorophenyl, chlorophenyl, bromophenyl,difluorophenyl, chlorofluorophenyl, dichlorophenyl, trifluorophenyl,trichlorophenyl, naphthyl, methylnaphtyl, methoxynaphthyl,fluoronaphthyl, chloronaphthyl or bromonaphthyl group; more preferably aphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl,4-trifluoromethoxyphenyl, 4-difluoromethoxyphenyl, 2-, 3- or4-fluorophenyl, 2-, 3- or 4-chlorophenyl, 4-bromophenyl, 2,4- or2,6-difluorophenyl, 4-cloro-2-fluorophenyl, 2-chloro-4-fluorophenyl,2,4- or 2,6-dichlorophenyl, 2,4,6-trifluorophenyl or2,4,6-trichlorophenyl group; still more preferably a 4-fluorophenyl,4-chlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl,4chloro-2-fluorophenyl, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl or2,6-dichlorophenyl group; and most preferably a 4-fluorophenyl,2,4-difluorophenyl or 4-chlorophenyl group.

The preferred group A is an oxygen atom or a sulfur atom; morepreferably an oxygen atom.

The compound of formula (I) in this invention can exist as an opticalisomer due to an asymmetric carbon atom(s) or as a geometrical isomerdue to a double bond(s) or to ring structure. The present inventionencompasses a single isomer and mixtures of such isomers.

The pharmaceutically acceptable salts of compounds of formula (I) areacid addition salts. Examples of such salt are, for example, ahydrohalogenic acid salt such as hydrofluoride, hydrochloride,hydrobromide, hydroiodide; a nitrate; a perchlorate; a sulfate; aphosphate; a carbonate; a C₁-C₆ alkylsulfonate which may be optionallysubstituted with fluorine atoms, such as methanesulfonate,trifluoromethanesulfonate, ethanesulfonate, pentafluoroethanesulfonate,propanesulfonate, butanesulfonate, pentanesulfonate, hexanesulfonate; aC₆-C₁₀ arylsulfonate such as benzenesulfonate, p-toluenesulfonate; acarboxylate such as acetate, propionate, lactate, benzoate, fumarate,maleate, succinate, citrate, tartrate, oxalate, malonate; or an aminoacid salt such as glutamate or aspartate; preferably a hydrochloride,sulfate or carboxylate and most preferably a hydrochloride.

The compounds of formula (I) in this invention or salts thereof canexist as hydrates. The present invention encompasses such hydrates.

Preferred compounds of formula (I) are:

(1) a compound wherein R¹ is a C₂-C₄ alkenyl group, a C₃-C₄ alkenylgroup substituted with fluoro or chloro, a C₃-C₆ cycloalkyl group whichmay be optionally substituted with C₁-C₂ alkyl or a C₃-C₆cycloalkyl-C₁-C₂ alkyl group which may be substituted with C₁-C₂ alkyl;

(2) a compound wherein R¹ is a C₃-C₄ alkenyl group, a3-chloro-2-propenyl group, a 3,3-difluoro-2-propenyl group, a3,3-dichloro-2-propenyl group, a cyclopropyl group, a2-methylcyclopropyl group, a 2-ethylcyclopropyl group, a cyclobutylgroup, a cyclopentyl group, a 2-methylcyclopentyl group, a cyclohexylgroup, a 2-methylcyclohexyl group, a cyclopropylmethyl group, a2-methylcyclopropylmethyl group, a 2-ethylcyclopropylmethyl group, acyclobutylmethyl group, a 2-methylcyclobutylmethyl group, acyclopentylmethyl group or a 2-methylcyclohexylmethyl group;

(3) a compound wherein R¹ is a 2-propenyl group, a 2-butenyl group, acyclopropyl group, a 2-methylcyclopropyl group, a cyclopentyl group, a2-methylcyclopentyl group, a cyclohexyl group, a 2-methylcyclohexylgroup, a cyclopropylmethyl group, a 2-methylcyclopropylmethyl group, acyclopentylmethyl group or a 2-methylcyclohexylmethyl group;

(4) a compound wherein R¹ is a 2-propenyl group, a 2-butenyl group, acyclopropyl group, a 2-methylcyclopropyl group, a cyclopropylmethylgroup or a 2-methylcyclopropylmethyl group;

(5) a compound wherein R¹ is a 2-butenyl group, a cyclopropylmethylgroup or a 2-methylcyclopropylmethyl group;

(6) a compound wherein R² is a C₁-C₄ alkyl group;

(7) a compound wherein R² is a C₁-C₂ alkyl group;

(8) a compound wherein R² is a methyl group;

(9) a compound wherein R³ is a hydroxymethyl group, a C₂-C₆ aliphaticacyloxymethyl group, a benzoyloxymethyl group which may be optionallysubstituted with methyl, methoxy, fluoro or chloro, a C₁-C₄alkoxycarbonyloxymethyl group, a formyl group, a carboxyl group, a C₁-C₄alkoxycarbonyl group or a phenyloxycarbonyl group which may beoptionally substituted with methyl, methoxy, fluoro or chloro;

(10) a compound wherein R³ is a hydroxymethyl group, a C₂-C₆ aliphaticacyloxymethyl group, a benzoyloxymethyl group, a C₁-C₂alkoxycarbonyloxymethyl group, a formyl group, a carboxyl group, a C₁-C₂alkoxycarbonyl group or a phenyloxycarbonyl group;

(11) a compound wherein R³ is a hydroxymethyl group, a C₂-C₄ aliphaticacyloxymethyl group, a C₁-C₂ alkoxycarbonyloxymethyl group, a formylgroup, a carboxyl group or a C₁-C₂ alkoxycarbonyl group;

(12) a compound wherein R³ is a hydroxymethyl group, a C₂-C₃ aliphaticacyloxymethyl group, a formyl group or a carboxyl group;

(13) a compound wherein R³ is a hydroxymethyl group or an acetoxymethylgroup;

(14) a compound wherein R⁴ is a phenyl group which is substituted with 1to 3 substituents selected from the group consisting of C₁-C₄ alkyl,halogeno C₁-C₄ alkyl, C₁-C₄ alkoxy, halogeno C₁-C₄ alkoxy, fluoro,chloro and bromo;

(15) a compound wherein R⁴ is a phenyl group which is substituted with 1to 3 substituents selected from the group consisting of methyl,trifluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy, fluoro,chloro and bromo;

(16) a compound wherein R⁴ is a phenyl group which is substituted at theposition(s) selected from the group consisting of 2-, 4- and 6-positionof the phenyl group with 1 or 2 substituents selected from the groupconsisting of fluoro and chloro;

(17) a compound wherein R⁴ is a phenyl group which is substituted at the4-position, 2,4-positions or 2,6-positions of the phenyl group with 1 or2 substituents selected from the group consisting of fluoro and chloro;

(18) a compound wherein A is an oxygen atom or a sufur atom; and

(19) a compound wherein A is an oxygen atom.

In each group of compounds (1)-(5), (6)-(8), (9)-(13), (14)-(17), or(18)-(19) described above, the larger the number of the compound is, themore preferable the compound, (similarly in the group of compounds(20)-(24) described below). Compounds wherein R¹, R², R³, R⁴ and A areoptionally selected from groups of compounds (1)-(5), (6)-(8), (9)-(13),(14)-(17), and (18)-(19), respectively, are a preferable.

Such compounds are as follows for example:

(20) a compound wherein R¹ is a C₂-C₄ alkenyl group, a C₃-C₄ alkenylgroup substituted with fluoro or chloro, a C₃-C₆ cycloalkyl group whichmay be optionally substituted with C₁-C₂ alkyl or a C₃-C₆cycloalkyl-C₁-C₂ alkyl group which may be substituted with C₁-C₂ alkyl,

R² is a C₁-C₄ alkyl group,

R³ is a hydroxymethyl group, a C₂-C₆ aliphatic acyloxymethyl group, abenzoyloxymethyl group which may be optionally substituted with methyl,methoxy, fluoro or chloro, a C₁-C₄ alkoxycarbonyloxymethyl group, aformyl group, a carboxyl group, a C₁-C₄ alkoxycarbonyl group or aphenyloxycarbonyl group which may be optionally substituted with methyl,methoxy, fluoro or chloro,

R⁴ is a phenyl group which is substituted with 1 to 3 substituentsselected from the group consisting of C₁-C₄ alkyl, halogeno C₁-C₄ alkyl,C₁-C₄ alkoxy, halogeno-C₁-C₄ alkoxy, fluoro, chloro and bromo,

A is an oxygen atom or a sufur atom;

(21) a compound wherein R¹ is a C₃-C₄ alkenyl group, a3-chloro-2-propenyl group, a 3,3-difluoro-2-propenyl, a3,3-dichloro-2-propenyl group, a cyclopropyl group, a 2-methylcyclpropylgroup, a 2-ethylcyclopropyl group, a cyclobutyl group, a cyclopentylgroup, a 2-methylcyclopentyl group, a cyclohexyl group, a2-methylcyclohexyl group, a cyclopropylmethyl group, a2-methylcyclopropylmethyl group, a 2-ethylcyclopropylmethyl group, acyclobutylmethyl group, a 2-methylcyclobutylmethyl group, acyclopentylmethyl group or a 2-methylcyclohexylmethyl group,

R² is a C₁-C₄ alkyl group,

R³ is a hydroxymethyl group, a C₂-C₆ aliphatic acyloxymethyl group, abenzoyloxymethyl group, a C₁-C₂ alkoxycarbonyloxymethyl group, a formylgroup, a carboxyl group, a C₁-C₂ alkoxycarbonyl group or aphenyloxycarbonyl group,

R⁴ is a phenyl group which is substituted with 1 to 3 substituentsselected from the group consisting of methyl, trifluoromethyl, methoxy,trifluoromethoxy, difluoromethoxy, fluoro, chloro and bromo,

A is an oxygen atom or a sulfur atom;

(22) a compound wherein R¹ is a 2-propenyl group, a 2-butenyl group, acyclopropyl group, a 2-methylcyclopropyl group, a cyclopentyl group, a2-methylcyclopentyl group, a cyclohexyl group, a 2-methylcyclohexylgroup, a cyclopropylmethyl group, a 2-methylcyclopropylmethyl group, acyclopentylmethyl group or a 2-methylcyclohexylmethyl group,

R² is a C₁-C₂ alkyl group,

R³ is a hydroxymethyl group, a C₂-C₄ aliphatic acyloxymethyl group, aC₁-C₂ alkoxycarbonyloxymethyl group, a formyl group, a carboxyl group ora C₁-C₂ alkoxycarbonyl group,

R⁴ is a phenyl group which is substituted at the position(s) selectedfrom the group consisting of 2-, 4- and 6-position of the phenyl groupwith 1 or 2 substituents selected from the group consisting of fluoroand chloro,

A is an oxygen atom;

(23) a compound wherein R¹ is a 2-propenyl group, a 2-butenyl group, acyclopropyl group, a 2-methylcyclopropyl group, a cyclopropylmethylgroup or a 2-methylcyclopropylmethyl group,

R² is a C₁-C₂ alkyl group,

R³ is a hydroxymethyl group, a C₂-C₃ aliphatic acyloxymethyl group, aformyl group or a carboxyl group,

R⁴ is a phenyl group which is substituted at the position(s) selectedfrom the group consisting of 2-, 4- and 6-position of the phenyl groupwith 1 or 2 substituents selected from the group consisting of fluoroand chloro,

A is an oxygen atom; and

(24) a compound wherein R¹ is a 2-butenyl group, a cyclopropylmethylgroup of a 2-methylcyclopropylmethyl group

R² is a methyl group,

R³ is a hydroxymethyl group or an acetoxymethyl group,

R⁴ is a phenyl group which is substituted at the 4position,2,4-positions or, 2,6-positions of the phenyl group with 1 or 2substituents selected from the group consisting of fluoro and chloro,

A is an oxygen atom.

Preferred compounds of formula (I) can be exemplified in Table 1.

TABLE 1 (I)

Exemp. Comp. No. R¹ R² R³ A R⁴ 1 CH═CHCH₃ Me CH₂OH O Ph 2 CH₂CH═CH₂ MeCH₂OH O Ph 3 CH₂C(CH₃)═CH₂ Me CH₂OH O Ph 4 CH₂CH═CHCH₃ Me CH₂OH O Ph 5CH₂CH═CF₂ Me CH₂OH O Ph 6 Pr^(c) Me CH₂OH O Ph 7 2-MePr^(c) Me CH₂OH OPh 8 CH₂Pr^(c) Me CH₂OH O Ph 9 CH₂(2-MePr^(c)) Me CH₂OH O Ph 10CH₂Bu^(c) Me CH₂OH O Ph 11 CH₂Pn^(c) Me CH₂OH O Ph 12 CH₂Hx^(c) Me CH₂OHO Ph 13 CH═CHCH₂ Me CH₂OH O 2-FPh 14 CH₂CH═CH₂ Me CH₂OH O 2-FPh 15CH₂CH═CHCH₃ Me CH₂OH O 2-FPh 16 CH₂Pr^(c) Me CH₂OH O 2-FPh 17CH₂(2-MePr^(c)) Me CH₂OH O 2-FPh 18 CH═CH₂ Me CH₂OH O 4-FPh 19 CH═CHCH₃Me CH₂OH O 4-FPh 20 CH₂CH═CH₂ Me CH₂OH O 4-FPh 21 CH₂C(CH₃)═CH₂ Me CH₂OHO 4-FPh 22 CH₂CH═CHCH₃ Me CH₂OH O 4-FPh 23 CH₂CH═CHCH₂CH₃ Me CH₂OH O4-FPh 24 CH₂CH═CF₂ Me CH₂OH O 4-FPh 25 CH₂CH═CHCl Me CH₂OH O 4-FPh 26CH₂CH═CCl₂ Me CH₂OH O 4-FPh 27 Pr^(c) Me CH₂OH O 4-FPh 28 2-MePr^(c) MeCH₂OH O 4-FPh 29 Bu^(c) Me CH₂OH O 4-FPh 30 Pn^(c) Me CH₂OH O 4-FPh 31Hx^(c) Me CH₂OH O 4-FPh 32 CH₂Pr^(c) Me CH₂OH O 4-FPh 33 CH₂(2-MePr^(c))Me CH₂OH O 4-FPh 34 CH₂CH₂Pr^(c) Me CH₂OH O 4-FPh 35 CH₂Bu^(c) Me CH₂OHO 4-FPh 36 CH₂Pn^(c) Me CH₂OH O 4-FPh 37 CH₂(2-MePn^(c)) Me CH₂OH O4-FPh 38 CH₂Hx^(c) Me CH₂OH O 4-FPh 39 CH₂(2-MeHx^(c)) Me CH₂OH O 4-FPh40 CH═CHCH₃ Me CH₂OH O 2,4-diFPh 41 CH₂CH═CH₂ Me CH₂OH O 2,4-diFPh 42CH₂C(CH₃)═CH₂ Me CH₂OH O 2,4-diFPh 43 CH₂CH═CHCH₃ Me CH₂OH O 2,4-diFPh44 CH₂CH═CF₂ Me CH₂OH O 2,4-diFPh 45 Pr^(c) Me CH₂OH O 2,4-diFPh 462-MePr^(c) Me CH₂OH O 2,4-diFPh 47 CH₂Pr^(c) Me CH₂OH O 2,4-diFPh 48CH₂(2-MePr^(c)) Me CH₂OH O 2,4-diFPh 49 CH₂Bu^(c) Me CH₂OH O 2,4-diFPh50 CH₂Pn^(c) Me CH₂OH O 2,4-diFPh 51 CH₂Hx^(c) Me CH₂OH O 2,4-diFPh 52CH═CHCH₃ Me CH₂OH O 2-ClPh 53 CH₂CH═CH₂ Me CH₂OH O 2-ClPh 54 CH₂CH═CHCH₃Me CH₂OH O 2-ClPh 55 CH₂Pr^(c) Me CH₂OH O 2-ClPh 56 CH₂(2-MePr^(c)) MeCH₂OH O 2-ClPh 57 CH═CHCH₃ Me CH₂OH O 4-ClPh 58 CH₂CH═CH₂ Me CH₂OH O4-ClPh 59 CH₂CH═CHCH₃ Me CH₂OH O 4-ClPh 60 CH₂Pr^(c) Me CH₂OH O 4-ClPh61 CH₂(2-MePr^(c)) Me CH₂OH O 4-ClPh 62 CH₂CH═CH₂ Me CH₂OH O 2-F,4-ClPh63 CH₂CH═CHCH₃ Me CH₂OH O 2-F,4-ClPh 64 CH₂Pr^(c) Me CH₂OH O 2-F,4-ClPh65 CH₂(2-MePr^(c)) Me CH₂OH O 2-F,4-ClPh 66 CH₂CH═CH₂ Me CH₂OH O2-Cl,4-FPh 67 CH₂CH═CHCH₃ Me CH₂OH O 2-Cl,4-FPh 68 CH₂Pr^(c) Me CH₂OH O2-Cl,4-FPh 69 CH₂(2-MePr^(c)) Me CH₂OH O 2-Cl,4-FPh 70 CH₂CH═CH₂ MeCH₂OH O 2,4-diClPh 71 CH₂CH═CHCH₃ Me CH₂OH O 2,4-diClPh 72 CH₂Pr^(c) MeCH₂OH O 2,4-diClPh 73 CH₂(2-MePr^(c)) Me CH₂OH O 2,4-diClPh 74 CH═CHCH₃Me CH₂OAc O Ph 75 CH₂CH═CH₂ Me CH₂OAc O Ph 76 CH₂C(CH₃)═CH₂ Me CH₂OAc OPh 77 CH₂CH═CHCH₃ Me CH₂OAc O Ph 78 CH₂CH═CF₂ Me CH₂OAc O Ph 79 Pr^(c)Me CH₂OAc O Ph 80 2-MePr^(c) Me CH₂OAc O Ph 81 CH₂Pr^(c) Me CH₂OAc O Ph82 CH₂(2-MePr^(c)) Me CH₂OAc O Ph 83 CH₂Bu^(c) Me CH₂OAc O Ph 84CH₂Pn^(c) Me CH₂OAc O Ph 85 CH₂Hx^(c) Me CH₂OAc O Ph 86 CH═CHCH₃ MeCH₂OAc O 2-FPh 87 CH₂CH═CH₂ Me CH₂OAc O 2-FPh 88 CH₂CH═CHCH₃ Me CH₂OAc O2-FPh 89 CH₂Pr^(c) Me CH₂OAc O 2-FPh 90 CH₂(2-MePr^(c)) Me CH₂OAc O2-FPh 91 CH═CH₂ Me CH₂OAc O 4-FPh 92 CH═CHCH₃ Me CH₂OAc O 4-FPh 93CH₂CH═CH₂ Me CH₂OAc O 4-FPh 94 CH₂C(CH₃)═CH₂ Me CH₂OAc O 4-FPh 95CH₂CH═CHCH₃ Me CH₂OAc O 4-FPh 96 CH₂CH═CHCH₂CH₃ Me CH₂OAc O 4-FPh 97CH₂CH═CF₂ Me CH₂OAc O 4-FPh 98 CH₂CH═CHCl Me CH₂OAc O 4-FPh 99CH₂CH═CCl₂ Me CH₂OAc O 4-FPh 100 Pr^(c) Me CH₂OAc O 4-FPh 101 2-MePr^(c)Me CH₂OAc O 4-FPh 102 Bu^(c) Me CH₂OAc O 4-FPh 103 Pn^(c) Me CH₂OAc O4-FPh 104 Hx^(c) Me CH₂OAc O 4-FPh 105 CH₂Pr^(c) Me CH₂OAc O 4-FPh 106CH₂(2-MePr^(c)) Me CH₂OAc O 4-FPh 107 CH₂CH₂Pr^(c) Me CH₂OAc O 4-FPh 108CH₂Bu^(c) Me CH₂OAc O 4-FPh 109 CH₂Pn^(c) Me CH₂OAc O 4-FPh 110CH₂(2-MePn^(c)) Me CH₂OAc O 4-FPh 111 CH₂Hx^(c) Me CH₂OAc O 4-FPh 112CH₂(2-MeHx^(c)) Me CH₂OAc O 4-FPh 113 CH═CHCH₃ Me CH₂OAc O 2,4-diFPh 114CH₂CH═CH₂ Me CH₂OAc O 2,4-diFPh 115 CH₂C(CH₃)═CH₂ Me CH₂OAc O 2,4-diFPh116 CH₂CH═CHCH₃ Me CH₂OAc O 2,4-diFPh 117 CH₂CH═CF₂ Me CH₂OAc O2,4-diFPh 118 Pr^(c) Me CH₂OAc O 2,4-diFPh 119 2-MePr^(c) Me CH₂OAc O2,4-diFPh 120 CH₂Pr^(c) Me CH₂OAc O 2,4-diFPh 121 CH₂(2-MePr^(c)) MeCH₂OAc O 2,4-diFPh 122 CH₂Bu^(c) Me CH₂OAc O 2,4-diFPh 123 CH₂Pn^(c) MeCH₂OAc O 2,4-diFPh 124 CH₂Hx^(c) Me CH₂OAc O 2,4-diFPh 125 CH═CHCH₃ MeCH₂OAc O 2-ClPh 126 CH₂CH═CH₂ Me CH₂OAc O 2-ClPh 127 CH₂CH═CHCH₃ MeCH₂OAc O 2-ClPh 128 CH₂Pr^(c) Me CH₂OAc O 2-ClPh 129 CH₂(2-MePr^(c)) MeCH₂OAc O 2-ClPh 130 CH═CHCH₃ Me CH₂OAc O 4-ClPh 131 CH₂CH═CH₂ Me CH₂OAcO 4-ClPh 132 CH₂CH═CHCH₃ Me CH₂OAc O 4-ClPh 133 CH₂Pr^(c) Me CH₂OAc O4-ClPh 134 CH₂(2-MePr^(c)) Me CH₂OAc O 4-ClPh 135 CH₂CH═CH₂ Me CH₂OAc O2-F,4-ClPh 136 CH₂CH═CHCH₃ Me CH₂OAc O 2-F,4-ClPh 137 CH₂Pr^(c) MeCH₂OAc O 2-F,4-ClPh 138 CH₂(2-MePr^(c)) Me CH₂OAc O 2-F,4-ClPh 139CH₂CH═CH₂ Me CH₂OAc O 2-Cl,4-FPh 140 CH₂CH═CHCH₃ Me CH₂OAc O 2-Cl,4-FPh141 CH₂Pr^(c) Me CH₂OAc O 2-Cl,4-FPh 142 CH₂(2-MePr^(c)) Me CH₂OAc O2-Cl,4-FPh 143 CH₂CH═CH₂ Me CH₂OAc O 2,4-diClPh 144 CH₂CH═CHCH₃ MeCH₂OAc O 2,4-diClPh 145 CH₂Pr^(c) Me CH₂OAc O 2,4-diClPh 146CH₂(2-MePr^(c)) Me CH₂OAc O 2,4-diClPh 147 CH═CHCH₃ Me CH₂OPrp O Ph 148CH₂CH═CH₂ Me CH₂OPrp O Ph 149 CH₂CH═CHCH₃ Me CH₂OPrp O Ph 150 CH₂CH═CF₂Me CH₂OPrP O Ph 151 Pr^(c) Me CH₂OPrp O Ph 152 2-MePr^(c) Me CH₂OPrp OPh 153 CH₂Pr^(c) Me CH₂OPrp O Ph 154 CH₂(2-MePr^(c)) Me CH₂OPrp O Ph 155CH₂CH═CH₂ Me CH₂OPrp O 2-FPh 156 CH₂CH═CHCH₃ Me CH₂OPrp O 2-FPh 157CH₂Pr^(c) Me CH₂OPrp O 2-FPh 158 CH₂(2-MePr^(c)) Me CH₂OPrp O 2-FPh 159CH═CHCH₃ Me CH₂OPrp O 4-FPh 160 CH₂CH═CH₂ Me CH₂OPrp O 4-FPh 161CH₂CH═CHCH₃ Me CH₂OPrp O 4-FPh 162 CH₂CH═CF₂ Me CH₂OPrp O 4-FPh 163CH₂CH═CHCl Me CH₂OPrp O 4-FPh 164 Pr^(c) Me CH₂OPrp O 4-FPh 1652-MePr^(c) Me CH₂OPrp O 4-FPh 166 CH₂Pr^(c) Me CH₂OPrp O 4-FPh 167CH₂(2-MePr^(c)) Me CH₂OPrp O 4-FPh 168 CH₂Bu^(c) Me CH₂OPrp O 4-FPh 169CH₂Pn^(c) Me CH₂OPrp O 4-FPh 170 CH₂Hx^(c) Me CH₂OPrp O 4-FPh 171CH═CHCH₃ Me CH₂OPrp O 2,4-diFPh 172 CH₂CH═CH₂ Me CH₂OPrp O 2,4-diFPh 173CH₂CH═CHCH₃ Me CH₂OPrp O 2,4-diFPh 174 CH₂CH═CF₂ Me CH₂OPrp O 2,4-diFPh175 Pr^(c) Me CH₂OPrp O 2,4-diFPh 176 2-MePr^(c) Me CH₂OPrp O 2,4-diFPh177 CH₂Pr^(c) Me CH₂OPrp O 2,4-diFPh 178 CH₂(2-MePr^(c)) Me CH₂OPrp O2,4-diFPh 179 CH═CHCH₃ Me CH₂OPrp O 2-ClPh 180 CH₂CH═CH₂ Me CH₂OPrp O2-ClPh 181 CH₂CH═CHCH₃ Me CH₂OPrp O 2-ClPh 182 CH₂Pr^(c) Me CH₂OPrp O2-ClPh 183 CH₂(2-MePr^(c)) Me CH₂OPrp O 2-ClPh 184 CH═CHCH₃ Me CH₂OPrp O4-ClPh 185 CH₂CH═CH₂ Me CH₂OPrp O 4-ClPh 186 CH₂CH═CHCH₃ Me CH₂OPrp O4-ClPh 187 CH₂Pr^(c) Me CH₂OPrp O 4-ClPh 188 CH₂(2-MePr^(c)) Me CH₂OPrpO 4-ClPh 189 CH₂CH═CH₂ Me CH₂OPrp O 2-F,4-ClPh 190 CH₂CH═CHCH₃ MeCH₂OPrp O 2-F,4-ClPh 191 CH₂Pr^(c) Me CH₂OPrp O 2-F,4-ClPh 192CH₂(2-MePr^(c)) Me CH₂OPrp O 2-F,4-ClPh 193 CH₂CH═CH₂ Me CH₂OPrp O2-Cl,4-FPh 194 CH₂CH═CHCH₃ Me CH₂OPrp O 2-Cl,4-FPh 195 CH₂Pr^(c) MeCH₂OPrp O 2-Cl,4-FPh 196 CH₂(2-MePr^(c)) Me CH₂OPrp O 2-Cl,4-FPh 197CH₂CH═CH₂ Me CH₂OPrp O 2,4-diClPh 198 CH₂CH═CHCH₃ Me CH₂OPrp O2,4-diClPh 199 CH₂Pr^(c) Me CH₂OPrp O 2,4-diClPh 200 CH₂(2-MePr^(c)) MeCH₂OPrp O 2,4-diClPh 201 CH₂CH═CH₂ Me CH₂OBur O Ph 202 CH₂CH═CHCH₃ MeCH₂OBur O Ph 203 CH₂Pr^(c) Me CH₂OBur O Ph 204 CH₂(2-MePr^(c)) MeCH₂OBur O Ph 205 CH₂CH═CH₂ Me CH₂OBur O 2-FPh 206 CH₂CH═CHCH₃ Me CH₂OBurO 2-FPh 207 CH₂Pr^(c) Me CH₂OBur O 2-FPh 208 CH₂(2-MePr^(c)) Me CH₂OBurO 2-FPh 209 CH═CHCH₃ Me CH₂OBur O 4-FPh 210 CH₂CH═CH₂ Me CH₂OBur O 4-FPh211 CH₂CH═CHCH₃ Me CH₂OBur O 4-FPh 212 CH₂CH═CF₂ Me CH₂OBur O 4-FPh 213Pr^(c) Me CH₂OBur O 4-FPh 214 2-MePr^(c) Me CH₂OBur O 4-FPh 215CH₂Pr^(c) Me CH₂OBur O 4-FPh 216 CH₂(2-MePr^(c)) Me CH₂OBur O 4-FPh 217CH₂Bu^(c) Me CH₂OBur O 4-FPh 218 CH₂Pn^(c) Me CH₂OBur O 4-FPh 219CH₂Hx^(c) Me CH₂OBur O 4-FPh 220 CH₂CH═CH₂ Me CH₂OBur O 2,4-diFPh 221CH₂CH═CHCH₃ Me CH₂OBur O 2,4-diFPh 222 Pr^(c) Me CH₂OBur O 2,4-diFPh 2232-MePr^(c) Me CH₂OBur O 2,4-diFPh 224 CH₂Pr^(c) Me CH₂OBur O 2,4-diFPh225 CH₂(2-MePr^(c)) Me CH₂OBur O 2,4-diFPh 226 CH₂CH═CH₂ Me CH₂OBur O2-ClPh 227 CH₂CH═CHCH₃ Me CH₂OBur O 2-ClPh 228 CH₂Pr^(c) Me CH₂OBur O2-ClPh 229 CH₂(2-MePr^(c)) Me CH₂OBur O 2-ClPh 230 CH₂CH═CH₂ Me CH₂OBurO 4-ClPh 231 CH₂CH═CHCH₃ Me CH₂OBur O 4-ClPh 232 CH₂Pr^(c) Me CH₂OBur O4-ClPh 233 CH₂(2-MePr^(c)) Me CH₂OBur O 4-ClPh 234 CH₂CH═CH₂ Me CH₂OBurO 2-F,4-ClPh 235 CH₂CH═CHCH₃ Me CH₂OBur O 2-F,4-ClPh 236 CH₂Pr^(c) MeCH₂OBur O 2-F,4-ClPh 237 CH₂(2-MePr^(c)) Me CH₂OBur O 2-F,4-ClPh 238CH₂CH═CH₂ Me CH₂OBur O 2-Cl,4-FPh 239 CH₂CH═CHCH₃ Me CH₂OBur O2-Cl,4-FPh 240 CH₂Pr^(c) Me CH₂OBur O 2-Cl,4-FPh 241 CH₂(2-MePr^(c)) MeCH₂OBur O 2-Cl,4-FPh 242 CH₂CH═CH₂ Me CH₂OBur O 2,4-diClPh 243CH₂CH═CHCH₃ Me CH₂OBur O 2,4-diClPh 244 CH₂Pr^(c) Me CH₂OBur O2,4-diClPh 245 CH₂(2-MePr^(c)) Me CH₂OBur O 2,4-diClPh 246 CH₂CH═CH₂ MeCH₂OCOPh O Ph 247 CH₂Pr^(c) Me CH₂OCOPh O Ph 248 CH₂(2-MePr^(c)) MeCH₂OCOPh O Ph 249 CH₂(2-MePr^(c)) Me CH₂OCO(4-Me)Ph O Ph 250 CH₂CH═CH₂Me CH₂OCOPh O 2-FPh 251 CH₂Pr^(c) Me CH₂OCOPh O 2-FPh 252CH₂(2-MePr^(c)) Me CH₂OCOPh O 2-FPh 253 CH₂(2-MePr^(c)) MeCH₂OCO(4-Me)Ph) O 2-FPh 254 CH═CHCH₃ Me CH₂OCOPh O 4-FPh 255 CH₂CH═CH₂Me CH₂OCOPh O 4-FPh 256 CH₂CH═CH₂ Me CH₂OCO(4-Me)Ph O 4-FPh 257CH₂CH═CHCH₃ Me CH₂OCOPh O 4-FPh 258 CH₂CH═CF₂ Me CH₂OCOPh O 4-FPh 259Pr^(c) Me CH₂OCOPh O 4-FPh 260 2-MePr^(c) Me CH₂OCOPh O 4-FPh 261CH₂Pr^(c) Me CH₂OCOPh O 4-FPh 262 CH₂Pr^(c) Me CH₂OCO(4-Me)Ph O 4-FPh263 CH₂(2-MePr^(c)) Me CH₂OCOPh O 4-FPh 264 CH₂(2-MePr^(c)) MeCH₂OCO(4-Me)Ph O 4-FPh 265 CH₂(2-MePr^(c)) Me CH₂OCO(4- O 4-FPh MeO)Ph266 CH₂(2-MePr^(c)) Me CH₂OCO(4-F)Ph O 4-FPh 267 CH₂(2-MePr^(c)) MeCH₂OCO(4-Cl)Ph O 4-FPh 268 CH₂Bu^(c) Me CH₂OCOPh O 4-FPh 269 CH₂Pn^(c)Me CH₂OCOPh O 4-FPh 270 CH₂Hx^(c) Me CH₂OCOPh O 4-FPh 271 CH₂CH═CH₂ MeCH₂OCOPh O 2,4-diFPh 272 CH₂CH═CH₂ Me CH₂OCO(4-Me)Ph O 2,4-diFPh 273CH₂CH═CHCH₃ Me CH₂OCOPh O 2,4-diFPh 274 Pr^(c) Me CH₂OCOPh O 2,4-diFPh275 CH₂Pr^(c) Me CH₂OCOPh O 2,4-diFPh 276 CH₂(2-MePr^(c)) Me CH₂OCOPh O2,4-diFPh 277 CH₂(2-MePr^(c)) Me CH₂OCO(4-Me)Ph O 2,4-diFPh 278CH₂CH═CH₂ Me CH₂OCOPh O 2-ClPh 279 CH₂Pr^(c) Me CH₂OCOPh O 2-ClPh 280CH₂(2-MePr^(c)) Me CH₂OCOPh O 2-ClPh 281 CH₂(2-MePr^(c)) MeCH₂OCO(4-Me)Ph O 2-ClPh 282 CH₂CH═CH₂ Me CH₂OCOPh O 4-ClPh 283CH₂CH═CHCH₃ Me CH₂OCOPh O 4-ClPh 284 CH₂Pr^(c) Me CH₂OCOPh O 4-ClPh 285CH₂(2-MePr^(c)) Me CH₂OCOPh O 4-ClPh 286 CH₂(2-MePr^(c)) MeCH₂OCO(4-Me)Ph O 4-ClPh 287 CH₂CH═CHCH₃ Me CH₂OCOPh O 2-F,4-ClPh 288CH₂Pr^(c) Me CH₂OCOPh O 2-F,4-ClPh 289 CH₂(2-MePr^(c)) Me CH₂OCOPh O2-F,4-ClPh 290 CH₂(2-MePr^(c)) Me CH₂OCO(4-Me)Ph O 2-F,4-ClPh 291CH₂CH═CHCH₃ Me CH₂OCOPh O 2-Cl,4-FPh 292 CH₂Pr^(c) Me CH₂OCOPh O2-Cl,4-FPh 293 CH₂(2-MePr^(c)) Me CH₂OCOPh O 2-Cl,4-FPh 294CH₂(2-MePr^(c)) Me CH₂OCO(4-Me)Ph O 2-Cl,4-FPh 295 CH₂CH═CHCH₃ MeCH₂OCOPh O 2,4-diClPh 296 CH₂Pr^(c) Me CH₂OCOPh O 2,4-diClPh 297CH₂(2-MePr^(c)) Me CH₂OCOPh O 2,4-diClPh 298 CH₂(2-MePr^(c)) MeCH₂OCO(4-Me)Ph O 2,4-diClPh 299 CH₂CH═CHCH₃ Me CH₂OCO₂Me O Ph 300CH₂Pr^(c) Me CH₂OCO₂Me O Ph 301 CH₂(2-MePr^(c)) Me CH₂OCO₂Me O Ph 302CH₂CH═CH₃ Me CH₂OCO₂Me O 2-FPh 303 CH₂Pr^(c) Me CH₂OCO₂Me O 2-FPh 304CH₂(2-MePr^(c)) Me CH₂OCO₂Me O 2-FPh 305 CH═CHCH₃ Me CH₂OCO₂Me O 4-FPh306 CH₂CH═CH₂ Me CH₂OCO₂Me O 4-FPh 307 CH₂CH═CHCH₃ Me CH₂OCO₂Me O 4-FPh308 Pr^(c) Me CH₂OCO₂Me O 4-FPh 309 2-MePr^(c) Me CH₂OCO₂Me O 4-FPh 310CH₂Pr^(c) Me CH₂OCO₂Me O 4-FPh 311 CH₂(2-MePr^(c)) Me CH₂OCO₂Me O 4-FPh312 CH₂Bu^(c) Me CH₂OCO₂Me O 4-FPh 313 CH₂Pn^(c) Me CH₂OCO₂Me O 4-FPh314 CH₂Hx^(c) Me CH₂OCO₂Me O 4-FPh 315 CH₂CH═CHCH₃ Me CH₂OCO₂Me O2,4-diFPh 316 CH₂Pr^(c) Me CH₂OCO₂Me O 2,4-diFPh 317 CH₂(2-MePr^(c)) MeCH₂OCO₂Me O 2,4-diFPh 318 CH₂CH═CHCH₃ Me CH₂OCO₂Me O 2-ClPh 319CH₂Pr^(c) Me CH₂OCO₂Me O 2-ClPh 320 CH₂(2-MePr^(c)) Me CH₂OCO₂Me O2-ClPh 321 CH₂CH═CHCH₃ Me CH₂OCO₂Me O 4-ClPh 322 CH₂Pr^(c) Me CH₂OCO₂MeO 4-ClPh 323 CH₂(2-MePr^(c)) Me CH₂OCO₂Me O 4-ClPh 324 CH₂CH═CHCH₃ MeCH₂OCO₂Me O 2-F,4-ClPh 325 CH₂Pr^(c) Me CH₂OCO₂Me O 2-F,4-ClPh 326CH₂(2-MePr^(c)) Me CH₂OCO₂Me O 2-F,4-ClPh 327 CH₂CH═CHCH₃ Me CH₂OCO₂Me O2-Cl,4-FPh 328 CH₂Pr^(c) Me CH₂OCO₂Me O 2-Cl,4-FPh 329 CH₂(2-MePr^(c))Me CH₂OCO₂Me O 2-Cl,4-FPh 330 CH₂CH═CHCH₃ Me CH₂OCO₂Me O 2,4-diClPh 331CH₂Pr^(c) Me CH₂OCO₂Me O 2,4-diClPh 332 CH₂(2-MePr^(c)) Me CH₂OCO₂Me O2,4-diClPh 333 CH₂CH═CHCH₃ Me CH₂OCO₂Et O Ph 334 CH₂Pr^(c) Me CH₂OCO₂EtO Ph 335 CH₂(2-MePr^(c)) Me CH₂OCO₂Et O Ph 336 CH₂CH═CHCH₃ Me CH₂OCO₂EtO 2-FPh 337 CH₂Pr^(c) Me CH₂OCO₂Et O 2-FPh 338 CH₂(2-MePr^(c)) MeCH₂OCO₂Et O 2-FPh 339 CH═CHCH₃ Me CH₂OCO₂Et O 4-FPh 340 CH₂CH═CH₂ MeCH₂OCO₂Et O 4-FPh 341 CH₂CH═CHCH₃ Me CH₂OCO₂Et O 4-FPh 342 Pr^(c) MeCH₂OCO₂Et O 4-FPh 343 2-MePr^(c) Me CH₂OCO₂Et O 4-FPh 344 CH₂Pr^(c) MeCH₂OCO₂Et O 4-FPh 345 CH₂(2-MePr^(c)) Me CH₂OCO₂Et O 4-FPh 346 CH₂Bu^(c)Me CH₂OCO₂Et O 4-FPh 347 CH₂Pn^(c) Me CH₂OCO₂Et O 4-FPh 348 CH₂Hx^(c) MeCH₂OCO₂Et O 4-FPh 349 CH₂CH═CHCH₃ Me CH₂OCO₂Et O 2,4-diFPh 350 CH₂Pr^(c)Me CH₂OCO₂Et O 2,4-diFPh 351 CH₂(2-MePr^(c)) Me CH₂OCO₂Et O 2,4-diFPh352 CH₂CH═CHCH₃ Me CH₂OCO₂Et O 2-ClPh 353 CH₂Pr^(c) Me CH₂OCO₂Et O2-ClPh 354 CH₂(2-MePr^(c)) Me CH₂OCO₂Et O 2-ClPh 355 CH₂CH═CHCH₃ MeCH₂OCO₂Et O 4-ClPh 356 CH₂Pr^(c) Me CH₂OCO₂Et O 4-ClPh 357CH₂(2-MePr^(c)) Me CH₂OCO₂Et O 4-ClPh 358 CH₂CH═CHCH₃ Me CH₂OCO₂Et O2-F,4-ClPh 359 CH₂Pr^(c) Me CH₂OCO₂Et O 2-F,4-ClPh 360 CH₂(2-MePr^(c))Me CH₂OCO₂Et O 2-F,4-ClPh 361 CH₂CH═CHCH₃ Me CH₂OCO₂Et O 2-Cl,4-FPh 362CH₂Pr^(c) Me CH₂OCO₂Et O 2-Cl,4-FPh 363 CH₂(2-MePr^(c)) Me CH₂OCO₂Et O2-Cl,4-FPh 364 CH₂CH═CHCH₃ Me CH₂OCO₂Et O 2,4-diClPh 365 CH₂Pr^(c) MeCH₂OCO₂Et O 2,4-diClPh 366 CH₂(2-MePr^(c)) Me CH₂OCO₂Et O 2,4-diClPh 367CH₂CH═CHCH₃ Me CH₂OCO₂Pr O Ph 368 CH₂(2-MePr^(c)) Me CH₂OCO₂Pr O Ph 369CH₂CH═CHCH₃ Me CH₂OCO₂Pr O 2-FPh 370 CH₂(2-MePr^(c)) Me CH₂OCO₂Pr O2-FPh 371 CH₂CH═CHCH₃ Me CH₂OCO₂Pr O 4-FPh 372 CH₂Pr^(c) Me CH₂OCO₂Pr O4-FPh 373 CH₂(2-MePr^(c)) Me CH₂OCO₂Pr O 4-FPh 374 CH₂Pn^(c) MeCH₂OCO₂Pr O 4-FPh 375 CH₂Hx^(c) Me CH₂OCO₂Pr O 4-FPh 376 CH₂CH═CHCH₃ MeCH₂OCO₂Pr O 2,4-diFPh 377 CH₂(2-MePr^(c)) Me CH₂OCO₂Pr O 2,4-diFPh 378CH₂CH═CHCH₃ Me CH₂OCO₂Pr O 2-ClPh 379 CH₂(2-MePr^(c)) Me CH₂OCO₂Pr O2-ClPh 380 CH₂CH═CHCH₃ Me CH₂OCO₂Pr O 4-ClPh 381 CH₂(2-MePr^(c)) MeCH₂OCO₂Pr O 4-ClPh 382 CH₂CH═CHCH₃ Me CH₂OCO₂Pr O 2-F,4-ClPh 383CH₂(2-MePr^(c)) Me CH₂OCO₂Pr O 2-F,4-ClPh 384 CH₂CH═CHCH₃ Me CH₂OCO₂Pr O2-Cl,4-FPh 385 CH₂(2-MePr^(c)) Me CH₂OCO₂Pr O 2-Cl,4-FPh 386 CH₂CH═CHCH₃Me CH₂OCO₂Pr O 2,4-diClPh 387 CH₂(2-MePr^(c)) Me CH₂OCO₂Pr O 2,4-diClPh388 CH₂CH═CHCH₃ Me CH₂OCO₂Bu O Ph 389 CH₂(2-MePr^(c)) Me CH₂OCO₂Bu O Ph390 CH₂CH═CHCH₃ Me CH₂OCO₂Bu O 2-FPh 391 CH₂(2-MePr^(c)) Me CH₂OCO₂Bu O2-FPh 392 CH₂CH═CHCH₃ Me CH₂OCO₂Bu O 4-FPh 393 CH₂Pr^(c) Me CH₂OCO₂Bu O4-FPh 394 CH₂(2-MePr^(c)) Me CH₂OCO₂Bu O 4-FPh 395 CH₂Pn^(c) MeCH₂OCO₂Bu O 4-FPh 396 CH₂Hx^(c) Me CH₂OCO₂Bu O 4-FPh 397 CH₂CH═CHCH₃ MeCH₂OCO₂Bu O 2,4-diFPh 398 CH₂(2-MePr^(c)) Me CH₂OCO₂Bu O 2,4-diFPh 399CH₂CH═CHCH₃ Me CH₂OCO₂Bu O 2-ClPh 400 CH₂(2-MePr^(c)) Me CH₂OCO₂Bu O2-ClPh 401 CH₂CH═CHCH₃ Me CH₂OCO₂Bu O 4-ClPh 402 CH₂(2-MePr^(c)) MeCH₂OCO₂Bu O 4-ClPh 403 CH₂CH═CHCH₃ Me CH₂OCO₂Bu O 2-F,4-ClPh 404CH₂(2-MePr^(c)) Me CH₂OCO₂Bu O 2-F,4-ClPh 405 CH₂CH═CHCH₃ Me CH₂OCO₂Bu O2-Cl,4-FPh 406 CH₂(2-MePr^(c)) Me CH₂OCO₂Bu O 2-Cl,4-FPh 407 CH₂CH═CHCH₃Me CH₂OCO₂Bu O 2,4-diClPh 408 CH₂(2-MePr^(c)) Me CH₂OCO₂Bu O 2,4-diClPh409 CH₂CH═CHCH₃ Me CHO O Ph 410 CH₂Pr^(c) Me CHO O Ph 411CH₂(2-MePr^(c)) Me CHO O Ph 412 CH₂CH═CHCH₃ Me CHO O 2-FPh 413 CH₂Pr^(c)Me CHO O 2-FPh 414 CH₂(2-MePr^(c)) Me CHO O 2-FPh 415 CH═CHCH₃ Me CHO O4-FPh 416 CH₂CH═CH₂ Me CHO O 4-FPh 417 CH₂CH═CHCH₃ Me CHO O 4-FPh 418Pr^(c) Me CHO O 4-FPh 419 2-MePr^(c) Me CHO O 4-FPh 420 CH₂Pr^(c) Me CHOO 4-FPh 421 CH₂(2-MePr^(c)) Me CHO O 4-FPh 422 CH₂Bu^(c) Me CHO O 4-FPh423 CH₂Pn^(c) Me CHO O 4-FPh 424 CH₂Hx^(c) Me CHO O 4-FPh 425CH₂CH═CHCH₃ Me CHO O 2,4-diFPh 426 CH₂Pr^(c) Me CHO O 2,4-diFPh 427CH₂(2-MePr^(c)) Me CHO O 2,4-diFPh 428 CH₂CH═CHCH₃ Me CHO O 2-ClPh 429CH₂Pr^(c) Me CHO O 2-ClPh 430 CH₂(2-MePr^(c)) Me CHO O 2-ClPh 431CH₂CH═CHCH₃ Me CHO O 4-ClPh 432 CH₂Pr^(c) Me CHO O 4-ClPh 433CH₂(2-MePr^(c)) Me CHO O 4-ClPh 434 CH₂CH═CHCH₃ Me CHO O 2-F,4-ClPh 435CH₂Pr^(c) Me CHO O 2-F,4-ClPh 436 CH₂(2-MePr^(c)) Me CHO O 2-F,4-ClPh437 CH₂CH═CHCH₃ Me CHO O 2-Cl,4-FPh 438 CH₂Pr^(c) Me CHO O 2-Cl,4-FPh439 CH₂(2-MePr^(c)) Me CHO O 2-Cl,4-FPh 440 CH₂CH═CHCH₃ Me CHO O2,4-diClPh 441 CH₂Pr^(c) Me CHO O 2,4-diClPh 442 CH₂(2-MePr^(c)) Me CHOO 2,4-diClPh 443 CH₂CH═CHCH₃ Me CO₂H O Ph 444 CH₂Pr^(c) Me CO₂H O Ph 445CH₂(2-MePr^(c)) Me CO₂H O Ph 446 CH₂CH═CH₂ Me CO₂H O 2-FPh 447 CH₂Pr^(c)Me CO₂H O 2-FPh 448 CH₂(2-MePr^(c)) Me CO₂H O 2-FPh 449 CH═CHCH₃ Me CO₂HO 4-FPh 450 CH₂CH═CH₂ Me CO₂H O 4-FPh 451 CH₂CH═CHCH₃ Me CO₂H O 4-FPh452 Pr^(c) Me CO₂H O 4-FPh 453 2-MePr^(c) Me CO₂H O 4-FPh 454 CH₂Pr^(c)Me CO₂H O 4-FPh 455 CH₂(2-MePr^(c)) Me CO₂H O 4-FPh 456 CH₂Bu^(c) MeCO₂H O 4-FPh 457 CH₂Pn^(c) Me CO₂H O 4-FPh 458 CH₂Hx^(c) Me CO₂H O 4-FPh459 CH₂CH═CHCH₃ Me CO₂H O 2,4-diFPh 460 CH₂Pr^(c) Me CO₂H O 2,4-diFPh461 CH₂(2-MePr^(c)) Me CO₂H O 2,4-diFPh 462 CH₂CH═CHCH₃ Me CO₂H O 2-ClPh463 CH₂Pr^(c) Me CO₂H O 2-ClPh 464 CH₂(2-MePr^(c)) Me CO₂H O 2-ClPh 465CH₂CH═CHCH₃ Me CO₂H O 4-ClPh 466 CH₂Pr^(c) Me CO₂H O 4-ClPh 467CH₂(2-MePr^(c)) Me CO₂H O 4-ClPh 468 CH₂CH═CHCH₃ Me CO₂H O 2-F,4-ClPh469 CH₂Pr^(c) Me CO₂H O 2-F,4-ClPh 470 CH₂(2-MePr^(c)) Me CO₂H O2-F,4-ClPh 471 CH₂CH═CHCH₃ Me CO₂H O 2-Cl,4-FPh 472 CH₂Pr^(c) Me CO₂H O2-Cl,4-FPh 473 CH₂(2-MePr^(c)) Me CO₂H O 2-Cl,4-FPh 474 CH₂CH═CHCH₃ MeCO₂H O 2,4-diClPh 475 CH₂Pr^(c) Me CO₂H O 2,4-diClPh 476 CH₂(2-MePr^(c))Me CO₂H O 2,4-diClPh 477 CH₂CH═CHCH₃ Me CO₂Me O Ph 478 CH₂(2-MePr^(c))Me CO₂Me O Ph 479 CH₂CH═CHCH₃ Me CO₂Me O 2-FPh 480 CH₂(2-MePr^(c)) MeCO₂Me O 2-FPh 481 CH═CHCH₃ Me CO₂Me O 4-FPh 482 CH₂CH═CH₂ Me CO₂Me O4-FPh 483 CH₂CH═CHCH₃ Me CO₂Me O 4-FPh 484 CH₂Pr^(c) Me CO₂Me O 4-FPh485 CH₂(2-MePr^(c)) Me CO₂Me O 4-FPh 486 CH₂CH═CHCH₃ Me CO₂Me O2,4-diFPh 487 CH₂Pr^(c) Me CO₂Me O 2,4-diFPh 488 CH₂(2-MePr^(c)) MeCO₂Me O 2,4-diFPh 489 CH₂CH═CHCH₃ Me CO₂Me O 2-ClPh 490 CH₂(2-MePr^(c))Me CO₂Me O 2-ClPh 491 CH₂CH═CHCH₃ Me CO₂Me O 4-ClPh 492 CH₂(2-MePr^(c))Me CO₂Me O 4-ClPh 493 CH₂CH═CHCH₃ Me CO₂Me O 2-F,4-ClPh 494CH₂(2-MePr^(c)) Me CO₂Me O 2-F,4-ClPh 495 CH₂CH═CHCH₃ Me CO₂Me O2-Cl,4-FPh 496 CH₂(2-MePr^(c)) Me CO₂Me O 2-Cl,4-FPh 497 CH₂CH═CHCH₃ MeCO₂Me O 2,4-diClPh 498 CH₂(2-MePr^(c)) Me CO₂Me O 2,4-diClPh 499CH₂CH═CHCH₃ Me CO₂Et O Ph 500 CH₂(2-MePr^(c)) Me CO₂Et O Ph 501CH₂CH═CHCH₃ Me CO₂Et O 2-FPh 502 CH₂(2-MePr^(c)) Me CO₂Et O 2-FPh 503CH₂CH═CH₂ Me CO₂Et O 4-FPh 504 CH₂CH═CHCH₃ Me CO₂Et O 4-FPh 505CH₂Pr^(c) Me CO₂Et O 4-FPh 506 CH₂(2-MePr^(c)) Me CO₂Et O 4-FPh 507CH₂CH═CHCH₃ Me CO₂Et O 2,4-diFPh 508 CH₂(2-MePr^(c)) Me CO₂Et O2,4-diFPh 509 CH₂CH═CHCH₃ Me CO₂Et O 2-ClPh 510 CH₂(2-MePr^(c)) Me CO₂EtO 2-ClPh 511 CH₂CH═CHCH₃ Me CO₂Et O 4-ClPh 512 CH₂(2-MePr^(c)) Me CO₂EtO 4-ClPh 513 CH₂CH═CHCH₃ Me CO₂Et O 2-F,4-ClPh 514 CH₂(2-MePr^(c)) MeCO₂Et O 2-F,4-ClPh 515 CH₂CH═CHCH₃ Me CO₂Et O 2-Cl,4-FPh 516CH₂(2-MePr^(c)) Me CO₂Et O 2-Cl,4-FPh 517 CH₂CH═CHCH₃ Me CO₂Et O2,4-diClPh 518 CH₂(2-MePr^(c)) Me CO₂Et O 2,4-diClPh 519 CH₂(2-MePr^(c))Me CO₂Pr O Ph 520 CH₂(2-MePr^(c)) Me CO₂Bu O Ph 521 CH₂CH═CHCH₃ Me CO₂PrO 2-FPh 522 CH₂CH═CHCH₃ Me CO₂Bu O 2-FPh 523 CH₂CH═CHCH₃ Me CO₂Ph O2-FPh 524 CH₂(2-MePr^(c)) Me CO₂Pr O 2-FPh 525 CH₂(2-MePr^(c)) Me CO₂BuO 2-FPh 526 CH₂(2-MePr^(c)) Me CO₂Ph O 2-FPh 527 CH₂(2-MePr^(c)) MeCO₂(4-Me)Ph O 2-FPh 528 CH₂CH═CH₂ Me CO₂Pr O 4-FPh 529 CH₂CH═CH₂ MeCO₂Bu O 4-FPh 530 CH₂CH═CH₂ Me CO₂Ph O 4-FPh 531 CH₂CH═CH₂ MeCO₂(4-Me)Ph O 4-FPh 532 CH₂CH═CHCH₃ Me CO₂Pr O 4-FPh 533 CH₂CH═CHCH₃ MeCO₂Bu O 4-FPh 534 CH₂CH═CHCH₃ Me CO₂Ph O 4-FPh 535 CH₂Pr^(c) Me CO₂Pr O4-FPh 536 CH₂Pr^(c) Me CO₂Bu O 4-FPh 537 CH₂Pr^(c) Me CO₂Ph O 4-FPh 538CH₂Pr^(c) Me CO₂(4-Me)Ph O 4-FPh 539 CH₂(2-MePr^(c)) Me CO₂Pr O 4-FPh540 CH₂(2-MePr^(c)) Me CO₂Bu O 4-FPh 541 CH₂(2-MePr^(c)) Me CO₂Ph O4-FPh 542 CH₂(2-MePr^(c)) Me CO₂(4-Me)Ph O 4-FPh 543 CH₂(2-MePr^(c)) MeCO₂(4-MeO)Ph O 4-FPh 544 CH₂(2-MePr^(c)) Me CO₂(4-F)Ph O 4-FPh 545CH₂(2-MePr^(c)) Me CO₂(4-Cl)Ph O 4-FPh 546 CH₂CH═CHCH₃ Me CO₂Pr O2,4-diFPh 547 CH₂CH═CHCH₃ Me CO₂Bu O 2,4-diFPh 548 CH₂(2-MePr^(c)) MeCO₂Pr O 2,4-diFPh 549 CH₂(2-MePr^(c)) Me CO₂Bu O 2,4-diFPh 550CH₂(2-MePr^(c)) Me CO₂Ph O 2,4-diFPh 551 CH₂CH═CHCH₃ Me CO₂Pr O 2-ClPh552 CH₂CH═CHCH₃ Me CO₂Bu O 2-ClPh 553 CH₂(2-MePr^(c)) Me CO₂Pr O 2-ClPh554 CH₂(2-MePr^(c)) Me CO₂Bu O 2-ClPh 555 CH₂(2-MePr^(c)) Me CO₂Ph O2-ClPh 556 CH₂CH═CHCH₃ Me CO₂Pr O 4-ClPh 557 CH₂CH═CHCH₃ Me CO₂Bu O4-ClPh 558 CH₂(2-MePr^(c)) Me CO₂Pr O 4-ClPh 559 CH₂(2-MePr^(c)) MeCO₂Bu O 4-ClPh 560 CH₂(2-MePr^(c)) Me CO₂Ph O 4-ClPh 561 CH₂CH═CHCH₃ MeCO₂Pr O 2-F,4-ClPh 562 CH₂(2-MePr^(c)) Me CO₂Pr O 2-F,4-ClPh 563CH₂CH═CH₂ Me CO₂Pr O 2-Cl,4-FPh 564 CH₂(2-MePr^(c)) Me CO₂Pr O2-Cl,4-FPh 565 CH₂CH═CH₂ Me CO₂Pr O 2,4-diClPh 566 CH₂(2-MePr^(c)) MeCO₂Pr O 2,4-diClPh 567 CH₂CH═CH₂ Et CH₂OH O Ph 568 CH₂CH═CH₂ Pr CH₂OH OPh 569 CH₂Pr^(c) Et CH₂OH O Ph 570 CH₂Pr^(c) Pr CH₂OH O Ph 571CH₂(2-MePr^(c)) Et CH₂OH O Ph 572 CH₂(2-MePr^(c)) Pr CH₂OH O Ph 573CH═CHCH₃ Et CH₂OH O 2-FPh 574 CH₂CH═CH₂ Et CH₂OH O 2-FPh 575 CH₂CH═CH₂Pr CH₂OH O 2-FPh 576 CH₂CH═CHCH₃ Et CH₂OH O 2-FPh 577 CH₂Pr^(c) Et CH₂OHO 2-FPh 578 CH₂Pr^(c) Pr CH₂OH O 2-FPh 579 CH₂(2-MePr^(c)) Et CH₂OH O2-FPh 580 CH₂(2-MePr^(c)) Pr CH₂OH O 2-FPh 581 CH₂(2-MePr^(c)) Bu CH₂OHO 2-FPh 582 CH═CH₂ Et CH₂OH O 4-FPh 583 CH═CHCH₃ Et CH₂OH O 4-FPh 584CH═CHCH₃ Pr CH₂OH O 4-FPh 585 CH₂CH═CH₂ Et CH₂OH O 4-FPh 586 CH₂CH═CH₂Pr CH₂OH O 4-FPh 587 CH₂CH═CH₂ Bu CH₂OH O 4-FPh 588 CH₂C(CH₃)═CH₂ EtCH₂OH O 4-FPh 589 CH₂CH═CHCH₃ Et CH₂OH O 4-FPh 590 CH₂CH═CHCH₃ Pr CH₂OHO 4-FPh 591 CH₂CH═CF₂ Et CH₂OH O 4-FPh 592 CH₂Pr^(c) Et CH₂OH O 4-FPh593 CH₂Pr^(c) Pr CH₂OH O 4-FPh 594 CH₂(2-MePr^(c)) Et CH₂OH O 4-FPh 595CH₂(2-MePr^(c)) Pr CH₂OH O 4-FPh 596 CH₂(2-MePr^(c)) Bu CH₂OH O 4-FPh597 CH₂Pn^(c) Et CH₂OH O 4-FPh 598 CH₂Hx^(c) Et CH₂OH O 4-FPh 599CH═CHCH₃ Et CH₂OH O 2,4-diFPh 600 CH₂CH═CH₂ Et CH₂OH O 2,4-diFPh 601CH₂CH═CH₂ Pr CH₂OH O 2,4-diFPh 602 CH₂CH═CHCH₃ Et CH₂OH O 2,4-diFPh 603CH₂CH═CF₂ Et CH₂OH O 2,4-diFPh 604 CH₂Pr^(c) Et CH₂OH O 2,4-diFPh 605CH₂Pr^(c) Pr CH₂OH O 2,4-diFPh 606 CH₂(2-MePr^(c)) Et CH₂OH O 2,4-diFPh607 CH₂(2-MePr^(c)) Pr CH₂OH O 2,4-diFPh 608 CH₂(2-MePr^(c)) Bu CH₂OH O2,4-diFPh 609 CH₂CH═CH₂ Et CH₂OAc O Ph 610 CH₂Pr^(c) Et CH₂OAc O Ph 611CH₂(2-MePr^(c)) Et CH₂OAc O Ph 612 CH₂(2-MePr^(c)) Pr CH₂OAc O Ph 613CH₂CH═CH₂ Et CH₂OAc O 2-FPh 614 CH₂Pr^(c) Et CH₂OAc O 2-FPh 615CH₂(2-MePr^(c)) Et CH₂OAc O 2-FPh 616 CH₂(2-MePr^(c)) Pr CH₂OAc O 2-FPh617 CH═CH₂ Et CH₂OAc O 4-FPh 618 CH═CHCH₃ Et CH₂OAc O 4-FPh 619CH₂CH═CH₂ Et CH₂OAc O 4-FPh 620 CH₂CH═CH₂ Pr CH₂OAc O 4-FPh 621CH₂CH═CHCH₃ Et CH₂OAc O 4-FPh 622 CH₂CH═CF₂ Et CH₂OAc O 4-FPh 623CH₂Pr^(c) Et CH₂OAc O 4-FPh 624 CH₂Pr^(c) Pr CH₂OAc O 4-FPh 625CH₂(2-MePr^(c)) Et CH₂OAc O 4-FPh 626 CH₂(2-MePr^(c)) Pr CH₂OAc O 4-FPh627 CH₂(2-MePr^(c)) Bu CH₂OAc O 4-FPh 628 CH₂CH═CH₂ Et CH₂OAc O2,4-diFPh 629 CH₂CH═CHCH₃ Et CH₂OAc O 2,4-diFPh 630 CH₂CH═CF₂ Et CH₂OAcO 2,4-diFPh 631 CH₂Pr^(c) Et CH₂OAc O 2,4-diFPh 632 CH₂Pr^(c) Pr CH₂OAcO 2,4-diFPh 633 CH₂(2-MePr^(c)) Et CH₂OAc O 2,4-diFPh 634CH₂(2-MePr^(c)) Pr CH₂OAc O 2,4-diFPh 635 CH₂CH═CH₂ Et CHO O Ph 636CH₂CH═CH₂ Et CO₂H O Ph 637 CH₂Pr^(c) Et CHO O Ph 638 CH₂Pr^(c) Et CO₂H OPh 639 CH₂(2-MePr^(c)) Et CHO O Ph 640 CH₂(2-MePr^(c)) Et CO₂H O Ph 641CH₂CH═CH₂ Et CHO O 2-FPh 642 CH₂CH═CH₂ Et CO₂H O 2-FPh 643 CH₂Pr^(c) EtCHO O 2-FPh 644 CH₂Pr^(c) Et CO₂H O 2-FPh 645 CH₂(2-MePr^(c)) Et CHO O2-FPh 646 CH₂(2-MePr^(c)) Et CO₂H O 2-FPh 647 CH═CHCH₃ Et CHO O 4-FPh648 CH═CHCH₃ Et CO₂H O 4-FPh 649 CH₂CH═CH₂ Et CHO O 4-FPh 650 CH₂CH═CH₂Et CO₂H O 4-FPh 651 CH₂CH═CH₂ Et CO₂Me O 4-FPh 652 CH₂CH═CH₂ Et CO₂Et O4-FPh 653 CH₂CH═CH₂ Pr CHO O 4-FPh 654 CH₂CH═CH₂ Pr CO₂H O 4-FPh 655CH₂CH═CHCH₃ Et CHO O 4-FPh 656 CH₂CH═CHCH₃ Et CO₂H O 4-FPh 657 CH₂CH═CF₂Et CHO O 4-FPh 658 CH₂CH═CF₂ Et CO₂H O 4-FPh 659 CH₂Pr^(c) Et CHO O4-FPh 660 CH₂Pr^(c) Et CO₂H O 4-FPh 661 CH₂Pr^(c) Et CO₂Me O 4-FPh 662CH₂Pr^(c) Et CO₂Et O 4-FPh 663 CH₂Pr^(c) Pr CHO O 4-FPh 664 CH₂Pr^(c) PrCO₂H O 4-FPh 665 CH₂(2-MePr^(c)) Et CHO O 4-FPh 666 CH₂(2-MePr^(c)) EtCO₂H O 4-FPh 667 CH₂(2-MePr^(c)) Et CO₂Me O 4-FPh 668 CH₂(2-MePr^(c)) EtCO₂Et O 4-FPh 669 CH₂(2-MePr^(c)) Pr CHO O 4-FPh 670 CH₂(2-MePr^(c)) PrCO₂H O 4-FPh 671 CH₂(2-MePr^(c)) Bu CHO O 4-FPh 672 CH₂(2-MePr^(c)) BuCO₂H O 4-FPh 673 CH₂CH═CH₂ Et CHO O 2,4-diFPh 674 CH₂CH═CH₂ Et CO₂H O2,4-diFPh 675 CH₂CH═CHCH₃ Et CHO O 2,4-diFPh 676 CH₂CH═CHCH₃ Et CO₂H O2,4-diFPh 677 CH₂CH═CF₂ Et CHO O 2,4-diFPh 678 CH₂CH═CF₂ Et CO₂H O2,4-diFPh 679 CH₂Pr^(c) Et CHO O 2,4-diFPh 680 CH₂Pr^(c) Et CO₂H O2,4-diFPh 681 CH₂(2-MePr^(c)) Et CHO O 2,4-diFPh 682 CH₂(2-MePr^(c)) EtCO₂H O 2,4-diFPh 683 CH₂(2-MePr^(c)) Et CO₂Me O 2,4-diFPh 684CH₂(2-MePr^(c)) Et CO₂Et O 2,4-diFPh 685 CH₂(2-MePr^(c)) Pr CHO O2,4-diFPh 686 CH₂(2-MePr^(c)) Pr CO₂H O 2,4-diFPh 687 CH₂CH═CH₂ Me CH₂OHO 4-MePh 688 CH₂CH═CH₂ Me CH₂OH O 4-CF₃Ph 689 CH₂CH═CH₂ Me CH₂OH O4-MeOPh 690 CH₂CH═CH₂ Me CH₂OH O 4-CHF₂OPh 691 CH₂CH═CH₂ Me CH₂OH O4-CF₃OPh 692 CH₂CH═CH₂ Me CH₂OH O 4-BrPh 693 CH₂CH═CHCH₃ Me CH₂OH O4-CF₃Ph 694 CH₂CH═CHCH₃ Me CH₂OH O 4-CHF₂OPh 695 CH₂CH═CHCH₃ Me CH₂OH O4-CF₃OPh 696 CH₂Pr^(c) Me CH₂OH O 4-MePh 697 CH₂Pr^(c) Me CH₂OH O4-CF₃Ph 698 CH₂Pr^(c) Me CH₂OH O 4-MeOPh 699 CH₂Pr^(c) Me CH₂OH O4-CHF₂OPh 700 CH₂Pr^(c) Me CH₂OH O 4-CF₃OPh 701 CH₂Pr^(c) Me CH₂OH O4-BrPh 702 CH₂(2-MePr^(c)) Me CH₂OH O 4-MePh 703 CH₂(2-MePr^(c)) MeCH₂OH O 4-CF₃Ph 704 CH₂(2-MePr^(c)) Me CH₂OH O 4-MeOPh 705CH₂(2-MePr^(c)) Me CH₂OH O 4-CHF₂OPh 706 CH₂(2-MePr^(c)) Me CH₂OH O4-CF₃OPh 707 CH₂(2-MePr^(c)) Me CH₂OH O 4-BrPh 708 CH₂CH═CH₂ Me CH₂OAc O4-MePh 709 CH₂CH═CH₂ Me CH₂OAc O 4-CF₃Ph 710 CH₂CH═CH₂ Me CH₂OAc O4-MeOPh 711 CH₂CH═CH₂ Me CH₂OAc O 4-CHF₂OPh 712 CH₂CH═CH₂ Me CH₂OAc O4-CF₃OPh 713 CH₂CH═CH₂ Me CH₂OAc O 4-BrPh 714 CH₂CH═CHCH₃ Me CH₂OAc O4-CF₃Ph 715 CH₂CH═CHCH₃ Me CH₂OAc O 4-CHF₂OPh 716 CH₂CH═CHCH₃ Me CH₂OAcO 4-CF₃OPh 717 CH₂Pr^(c) Me CH₂OAc O 4-MePh 718 CH₂Pr^(c) Me CH₂OAc O4-CF₃Ph 719 CH₂Pr^(c) Me CH₂OAc O 4-MeOPh 720 CH₂Pr^(c) Me CH₂OAc O4-CHF₂OPh 721 CH₂Pr^(c) Me CH₂OAc O 4-CF₃OPh 722 CH₂Pr^(c) Me CH₂OAc O4-BrPh 723 CH₂(2-MePr^(c)) Me CH₂OAc O 4-MePh 724 CH₂(2-MePr^(c)) MeCH₂OAc O 4-CF₃Ph 725 CH₂(2-MePr^(c)) Me CH₂OAc O 4-MeOPh 726CH₂(2-MePr^(c)) Me CH₂OAc O 4-CHF₂OPh 727 CH₂(2-MePr^(c)) Me CH₂OAc O4-CF₃OPh 728 CH₂(2-MePr^(c)) Me CH₂OAc O 4-BrPh 729 CH₂CH═CH₂ Me CH₂OPrpO 4-CF₃Ph 730 CH₂CH═CH₂ Me CH₂OBur O 4-CF₃Ph 731 CH₂CH═CH₂ Me CH₂OCO₂MeO 4-CF₃Ph 732 CH₂CH═CH₂ Me CH₂OCO₂Et O 4-CF₃Ph 733 CH₂CH═CH₂ Me CHO O4-CF₃Ph 734 CH₂CH═CH₂ Me CO₂H O 4-CF₃Ph 735 CH₂CH═CH₂ Me CO₂Me O 4-CF₃Ph736 CH₂CH═CH₂ Me CO₂Et O 4-CF₃Ph 737 CH₂CH═CH₂ Me CH₂OPrp O 4-CF₃OPh 738CH₂CH═CH₂ Me CH₂OBur O 4-CF₃OPh 739 CH₂CH═CH₂ Me CH₂OCO₂Me O 4-CF₃OPh740 CH₂CH═CH₂ Me CH₂OCO₂Et O 4-CF₃OPh 741 CH₂CH═CH₂ Me CHO O 4-CF₃OPh742 CH₂CH═CH₂ Me CO₂H O 4-CF₃OPh 743 CH₂CH═CH₂ Me CO₂Me O 4-CF₃OPh 744CH₂CH═CH₂ Me CO₂Et O 4-CF₃OPh 745 CH₂Pr^(c) Me CH₂OPrp O 4-CF₃Ph 746CH₂Pr^(c) Me CH₂OBur O 4-CF₃Ph 747 CH₂Pr^(c) Me CH₂OCO₂Me O 4-CF₃Ph 748CH₂Pr^(c) Me CH₂OCO₂Et O 4-CF₃Ph 749 CH₂Pr^(c) Me CHO O 4-CF₃Ph 750CH₂Pr^(c) Me CO₂H O 4-CF₃Ph 751 CH₂Pr^(c) Me CO₂Me O 4-CF₃Ph 752CH₂Pr^(c) Me CO₂Et O 4-CF₃Ph 753 CH₂Pr^(c) Me CH₂OPrp O 4-CF₃OPh 754CH₂Pr^(c) Me CH₂OBur O 4-CF₃OPh 755 CH₂Pr^(c) Me CH₂OCO₂Me O 4-CF₃OPh756 CH₂Pr^(c) Me CH₂OCO₂Et O 4-CF₃OPh 757 CH₂Pr^(c) Me CHO O 4-CF₃OPh758 CH₂Pr^(c) Me CO₂H O 4-CF₃OPh 759 CH₂Pr^(c) Me CO₂Me O 4-CF₃OPh 760CH₂Pr^(c) Me CO₂Et O 4-CF₃OPh 761 CH₂(2-MePr^(c)) Me CH₂OPrp O 4-MePh762 CH₂(2-MePr^(c)) Me CH₂OBur O 4-MePh 763 CH₂(2-MePr^(c)) Me CH₂OCO₂MeO 4-MePh 764 CH₂(2-MePr^(c)) Me CH₂OCO₂Et O 4-MePh 765 CH₂(2-MePr^(c))Me CHO O 4-MePh 766 CH₂(2-MePr^(c)) Me CO₂H O 4-MePh 767 CH₂(2-MePr^(c))Me CH₂OPrp O 4-CF₃Ph 768 CH₂(2-MePr^(c)) Me CH₂OBur O 4-CF₃Ph 769CH₂(2-MePr^(c)) Me CH₂OCOPh O 4-CF₃Ph 770 CH₂(2-MePr^(c)) Me CH₂OCO₂Me O4-CF₃Ph 771 CH₂(2-MePr^(c)) Me CH₂OCO₂Et O 4-CF₃Ph 772 CH₂(2-MePr^(c))Me CH₂OCO₂Pr O 4-CF₃Ph 773 CH₂(2-MePr^(c)) Me CHO O 4-CF₃Ph 774CH₂(2-MePr^(c)) Me CO₂H O 4-CF₃Ph 775 CH₂(2-MePr^(c)) Me CO₂Me O 4-CF₃Ph776 CH₂(2-MePr^(c)) Me CO₂Et O 4-CF₃Ph 777 CH₂(2-MePr^(c)) Me CO₂Ph O4-CF₃Ph 778 CH₂(2-MePr^(c)) Me CH₂OPrp O 4-MeOPh 779 CH₂(2-MePr^(c)) MeCH₂OBur O 4-MeOPh 780 CH₂(2-MePr^(c)) Me CH₂OCO₂Me O 4-MeOPh 781CH₂(2-MePr^(c)) Me CH₂OCO₂Et O 4-MeOPh 782 CH₂(2-MePr^(c)) Me CHO O4-MeOPh 783 CH₂(2-MePr^(c)) Me CO₂H O 4-MeOPh 784 CH₂(2-MePr^(c)) MeCH₂OPrp O 4-CHF₂OPh 785 CH₂(2-MePr^(c)) Me CH₂OBur O 4-CHF₂OPh 786CH₂(2-MePr^(c)) Me CH₂OCO₂Me O 4-CHF₂OPh 787 CH₂(2-MePr^(c)) MeCH₂OCO₂Et O 4-CHF₂OPh 788 CH₂(2.MePr^(c)) Me CHO O 4-CHF₂OPh 789CH₂(2.MePr^(c)) Me CO₂H O 4-CHF₂OPh 790 CH₂(2-MePr^(c)) Me CH₂OPrp O4-CF₃OPh 791 CH₂(2-MePr^(c)) Me CH₂OBur O 4-CF₃OPh 792 CH₂(2-MePr^(c))Me CH₂OCOPh O 4-CF₃OPh 793 CH₂(2-MePr^(c)) Me CH₂OCO₂Me O 4-CF₃OPh 794CH₂(2-MePr^(c)) Me CH₂OCO₂Et O 4-CF₃OPh 795 CH₂(2-MePr^(c)) Me CH₂OCO₂PrO 4-CF₃OPh 796 CH₂(2-MePr^(c)) Me CHO O 4-CF₃OPh 797 CH₂(2-MePr^(c)) MeCO₂H O 4-CF₃OPh 798 CH₂(2-MePr^(c)) Me CO₂Me O 4-CF₃OPh 799CH₂(2-MePr^(c)) Me CO₂Et O 4-CF₃OPh 800 CH₂(2-MePr^(c)) Me CO₂Ph O4-CF₃OPh 801 CH₂(2-MePr^(c)) Me CH₂OPrp O 4-BrPh 802 CH₂(2-MePr^(c)) MeCH₂OBur O 4-BrPh 803 CH₂(2-MePr^(c)) Me CH₂OCO₂Me O 4-BrPh 804CH₂(2-MePr^(c)) Me CH₂OCO₂Et O 4-BrPh 805 CH₂(2-MePr^(c)) Me CHO O4-BrPh 806 CH₂(2-MePr^(c)) Me CO₂H O 4-BrPh 807 CH₂CH═CH₂ Me CH₂OH S Ph808 CH₂CH═CH₂ Me CH₂OH NH Ph 809 CH₂CH═CHCH₃ Me CH₂OH S Ph 810 CH₂Pr^(c)Me CH₂OH S Ph 811 CH₂Pr^(c) Me CH₂OH NH Ph 812 CH₂(2-MePr^(c)) Me CH₂OHS Ph 813 CH₂(2-MePr^(c)) Me CH₂OH NH Ph 814 CH₂CH═CH₂ Me CH₂OH S 2-FPh815 CH₂CH═CH₂ Me CH₂OH NH 2-FPh 816 CH₂CH═CHCH₃ Me CH₂OH S 2-FPh 817CH₂Pr^(c) Me CH₂OH S 2-FPh 818 CH₂Pr^(c) Me CH₂OH NH 2-FPh 819CH₂(2-MePr^(c)) Me CH₂OH S 2-FPh 820 CH₂(2-MePr^(c)) Me CH₂OH NH 2-FPh821 CH═CHCH₃ Me CH₂OH S 4-FPh 822 CH₂CH═CH₂ Me CH₂OH S 4-FPh 823CH₂CH═CH₂ Me CH₂OH NH 4-FPh 824 CH₂C(CH₃)═CH₂ Me CH₂OH S 4-FPh 825CH₂CH═CHCH₃ Me CH₂OH S 4-FPh 826 CH₂CH═CHCH₃ Me CH₂OH NH 4-FPh 827CH₂CH═CF₂ Me CH₂OH S 4-FPh 828 CH₂CH═CHCl Me CH₂OH S 4-FPh 829CH₂CH═CCl₂ Me CH₂OH S 4-FPh 830 Pr^(c) Me CH₂OH S 4-FPh 831 2-MePr^(c)Me CH₂OH S 4-FPh 832 CH₂Pr^(c) Me CH₂OH S 4-FPh 833 CH₂Pr^(c) Me CH₂OHNH 4-FPh 834 CH₂(2-MePr^(c)) Me CH₂OH S 4-FPh 835 CH₂(2-MePr^(c)) MeCH₂OH NH 4-FPh 836 CH₂Bu^(c) Me CH₂OH S 4-FPh 837 CH₂Pn^(c) Me CH₂OH S4-FPh 838 CH₂(2-MePn^(c)) Me CH₂OH S 4-FPh 839 CH₂Hx^(c) Me CH₂OH S4-FPh 840 CH₂(2-MeHx^(c)) Me CH₂OH S 4-FPh 841 CH₂CH═CH₂ Me CH₂OH S2,4-diFPh 842 CH₂CH═CH₂ Me CH₂OH NH 2,4-diFPh 843 CH₂CH═CHCH₃ Me CH₂OH S2,4-diFPh 844 CH₂CH═CHCH₃ Me CH₂OH NH 2,4-diFPh 845 CH₂Pr^(c) Me CH₂OH S2,4-diFPh 846 CH₂(2-MePr^(c)) Me CH₂OH S 2,4-diFPh 847 CH₂(2-MePr^(c))Me CH₂OH NH 2,4-diFPh 848 CH₂Bu^(c) Me CH₂OH S 2,4-diFPh 849 CH₂Pn^(c)Me CH₂OH S 2,4-diFPh 850 CH₂Hx^(c) Me CH₂OH S 2,4-diFPh 851 CH₂CH═CH₂ MeCH₂OH S 2-ClPh 852 CH₂Pr^(c) Me CH₂OH S 2-ClPh 853 CH₂(2-MePr^(c)) MeCH₂OH S 2-ClPh 854 CH₂(2-MePr^(c)) Me CH₂OH NH 2-ClPh 855 CH₂CH═CH₂ MeCH₂OH S 4-ClPh 856 CH₂CH═CHCH₃ Me CH₂OH S 4-ClPh 857 CH₂Pr^(c) Me CH₂OHS 4-ClPh 858 CH₂(2-MePr^(c)) Me CH₂OH S 4-ClPh 859 CH₂(2-MePr^(c)) MeCH₂OH NH 4-ClPh 860 CH₂CH═CH₂ Me CH₂OH S 2,4-diClPh 861 CH₂Pr^(c) MeCH₂OH S 2,4-diClPh 862 CH₂(2-MePr^(c)) Me CH₂OH S 2,4-diClPh 863CH₂CH═CH₂ Me CH₂OAc S Ph 864 CH₂CH═CH₂ Me CH₂OAc NH Ph 865 CH₂CH═CHCH₃Me CH₂OAc S Ph 866 CH₂Pr^(c) Me CH₂OAc S Ph 867 CH₂(2-MePr^(c)) MeCH₂OAc S Ph 868 CH₂(2-MePr^(c)) Me CH₂OAc NH Ph 869 CH₂CH═CH₂ Me CH₂OAcS 2-FPh 870 CH₂CH═CH₂ Me CH₂OAc NH 2-FPh 871 CH₂CH═CHCH₃ Me CH₂OAc S2-FPh 872 CH₂Pr^(c) Me CH₂OAc S 2-FPh 873 CH₂(2-MePr^(c)) Me CH₂OAc S2-FPh 874 CH₂(2-MePr^(c)) Me CH₂OAc NH 2-FPh 875 CH═CH₂ Me CH₂OAc S4-FPh 876 CH═CHCH₃ Me CH₂OAc S 4-FPh 877 CH₂CH═CH₂ Me CH₂OAc S 4-FPh 878CH₂CH═CH₂ Me CH₂OAc NH 4-FPh 879 CH₂C(CH₃)═CH₂ Me CH₂OAc S 4-FPh 880CH₂CH═CHCH₃ Me CH₂OAc S 4-FPh 881 CH₂CH═CHCH₃ Me CH₂OAc NH 4-FPh 882CH₂CH═CF₂ Me CH₂OAc S 4-FPh 883 CH₂CH═CHCl Me CH₂OAc S 4-FPh 884CH₂CH═CCl₂ Me CH₂OAc S 4-FPh 885 Pr^(c) Me CH₂OAc S 4-FPh 886 2-MePr^(c)Me CH₂OAc S 4-FPh 887 CH₂Pr^(c) Me CH₂OAc S 4-FPh 888 CH₂Pr^(c) MeCH₂OAc NH 4-FPh 889 CH₂(2-MePr^(c)) Me CH₂OAc S 4-FPh 890CH₂(2-MePr^(c)) Me CH₂OAc NH 4-FPh 891 CH₂Bu^(c) Me CH₂OAc S 4-FPh 892CH₂Pn^(c) Me CH₂OAc S 4-FPh 893 CH₂(2-MePn^(c)) Me CH₂OAc S 4-FPh 894CH₂Hx^(c) Me CH₂OAc S 4-FPh 895 CH₂(2-MeHx^(c)) Me CH₂OAc S 4-FPh 896CH₂CH═CH₂ Me CH₂OAc S 2,4-diFPh 897 CH₂CH═CH₂ Me CH₂OAc NH 2,4-diFPh 898CH₂CH═CHCH₃ Me CH₂OAc S 2,4-diFPh 899 CH₂CH═CF₂ Me CH₂OAc S 2,4-diFPh900 CH₂Pr^(c) Me CH₂OAc S 2,4-diFPh 901 CH₂(2-MePr^(c)) Me CH₂OAc S2,4-diFPh 902 CH₂(2-MePr^(c)) Me CH₂OAc NH 2,4-diFPh 903 CH₂CH═CH₂ MeCH₂OAc S 2-ClPh 904 CH₂CH═CH₂ Me CH₂OAc NH 2-ClPh 905 CH₂CH═CHCH₃ MeCH₂OAc S 2-ClPh 906 CH₂Pr^(c) Me CH₂OAc S 2-ClPh 907 CH₂(2-MePr^(c)) MeCH₂OAc S 2-ClPh 908 CH₂(2-MePr^(c)) Me CH₂OAc NH 2-ClPh 909 CH₂CH═CH₂ MeCH₂OAc S 4-ClPh 910 CH₂CH═CH₂ Me CH₂OAc NH 4-ClPh 911 CH₂CH═CHCH₃ MeCH₂OAc S 4-ClPh 912 CH₂Pr^(c) Me CH₂OAc S 4-ClPh 913 CH₂(2-MePr^(c)) MeCH₂OAc S 4-ClPh 914 CH₂(2-MePr^(c)) Me CH₂OAc NH 4-ClPh 915 CH₂CH═CH₂ MeCH₂OAc S 2,4-diClPh 916 CH₂Pr^(c) Me CH₂OAc S 2,4-diClPh 917CH₂(2-MePr^(c)) Me CH₂OAc S 2,4-diClPh 918 CH₂CH═CH₂ Me CH₂OPrp S Ph 919CH₂Pr^(c) Me CH₂OPrp S Ph 920 CH₂(2-MePr^(c)) Me CH₂OPrp S Ph 921CH₂(2-MePr^(c)) Me CH₂OPrp NH Ph 922 CH₂CH═CH₂ Me CH₂OPrp S 2-FPh 923CH₂Pr^(c) Me CH₂OPrp S 2-FPh 924 CH₂(2-MePr^(c)) Me CH₂OPrp S 2-FPh 925CH₂(2-MePr^(c)) Me CH₂OPrp NH 2-FPh 926 CH₂CH═CH₂ Me CH₂OPrp S 4-FPh 927CH₂CH═CH₂ Me CH₂OPrp NH 4-FPh 928 CH₂CH═CHCH₃ Me CH₂OPrp S 4-FPh 929CH₂Pr^(c) Me CH₂OPrp S 4-FPh 930 CH₂(2-MePr^(c)) Me CH₂OPrp S 4-FPh 931CH₂(2-MePr^(c)) Me CH₂OPrp NH 4-FPh 932 CH₂Bu^(c) Me CH₂OPrp S 4-FPh 933CH₂Pn^(c) Me CH₂OPrp S 4-FPh 934 CH₂Hx^(c) Me CH₂OPrp S 4-FPh 935CH₂CH═CH₂ Me CH₂OPrp S 2,4-diFPh 936 CH₂CH═CH₂ Me CH₂OPrp NH 2,4-diFPh937 CH₂CH═CHCH₃ Me CH₂OPrp S 2,4-diFPh 938 CH₂Pr^(c) Me CH₂OPrp S2,4-diFPh 939 CH₂(2-MePr^(c)) Me CH₂OPrp S 2,4-diFPh 940 CH₂(2-MePr^(c))Me CH₂OPrp NH 2,4-diFPh 941 CH₂CH═CH₂ Me CH₂OPrp S 2-ClPh 942 CH₂Pr^(c)Me CH₂OPrp S 2-ClPh 943 CH₂(2-MePr^(c)) Me CH₂OPrp S 2-ClPh 944CH₂(2-MePr^(c)) Me CH₂OPrp NH 2-ClPh 945 CH₂CH═CH₂ Me CH₂OPrp S 4-ClPh946 CH₂Pr^(c) Me CH₂OPrp S 4-ClPh 947 CH₂(2-MePr^(c)) Me CH₂OPrp S4-ClPh 948 CH₂(2-MePr^(c)) Me CH₂OPrp NH 4-ClPh 949 CH₂CH═CH₂ Me CH₂OPrpS 2,4-diClPh 950 CH₂Pr^(c) Me CH₂OPrp S 2,4-diClPh 951 CH₂(2-MePr^(c))Me CH₂OPrp S 2,4-diClPh 952 CH₂(2-MePr^(c)) Me CH₂OBur S Ph 953CH₂CH═CH₂ Me CH₂OBur S 2-FPh 954 CH₂Pr^(c) Me CH₂OBur S 2-FPh 955CH₂(2-MePr^(c)) Me CH₂OBur S 2-FPh 956 CH₂CH═CH₂ Me CH₂OBur S 4-FPh 957CH₂CH═CH₂ Me CH₂OBur NH 4-FPh 958 CH₂CH═CHCH₃ Me CH₂OBur S 4-FPh 959Pr^(c) Me CH₂OBur S 4-FPh 960 2-MePr^(c) Me CH₂OBur S 4-FPh 961CH₂Pr^(c) Me CH₂OBur S 4-FPh 962 CH₂(2-MePr^(c)) Me CH₂OBur S 4-FPh 963CH₂(2-MePr^(c)) Me CH₂OBur NH 4-FPh 964 CH₂Bu^(c) Me CH₂OBur S 4-FPh 965CH₂Pn^(c) Me CH₂OBur S 4-FPh 966 CH₂Hx^(c) Me CH₂OBur S 4-FPh 967CH₂CH═CH₂ Me CH₂OBur S 2,4-diFPh 968 CH₂CH═CH₂ Me CH₂OBur NH 2,4-diFPh969 CH₂Pr^(c) Me CH₂OBur S 2,4-diFPh 970 CH₂(2-MePr^(c)) Me CH₂OBur S2,4-diFPh 971 CH₂(2-MePr^(c)) Me CH₂OBur NH 2,4-diFPh 972 CH₂CH═CH₂ MeCH₂OBur S 2-ClPh 973 CH₂Pr^(c) Me CH₂OBur S 2-ClPh 974 CH₂(2-MePr^(c))Me CH₂OBur S 2-ClPh 975 CH₂(2-MePr^(c)) Me CH₂OBur NH 2-ClPh 976CH₂CH═CH₂ Me CH₂OBur S 4-ClPh 977 CH₂Pr^(c) Me CH₂OBur S 4-ClPh 978CH₂(2-MePr^(c)) Me CH₂OBur S 4-ClPh 979 CH₂(2-MePr^(c)) Me CH₂OBur NH4-ClPh 980 CH₂CH═CH₂ Me CH₂OBur S 2,4-diClPh 981 CH₂Pr^(c) Me CH₂OBur S2,4-diClPh 982 CH₂(2-MePr^(c)) Me CH₂OBur S 2,4-diClPh 983CH₂(2-MePr^(c)) Me CH₂OBur NH 2,4-diClPh 984 CH₂(2.MePr^(c)) Me CH₂OCOPhS Ph 985 CH₂CH═CH₂ Me CH₂OCOPh S 2-FPh 986 CH₂(2-MePr^(c)) Me CH₂OCOPh S2-FPh 987 CH₂CH═CH₂ Me CH₂OCOPh S 4-FPh 988 CH₂CH═CHCH₃ Me CH₂OCOPh S4-FPh 989 CH₂Pr^(c) Me CH₂OCOPh S 4-FPh 990 CH₂(2-MePr^(c)) Me CH₂OCOPhS 4-FPh 991 CH₂(2-MePr^(c)) Me CH₂OCOPh NH 4-FPh 992 CH₂CH═CH₂ MeCH₂OCOPh S 2,4-diFPh 993 CH₂CH═CHCH₃ Me CH₂OCOPh S 2,4-diFPh 994CH₂Pr^(c) Me CH₂OCOPh S 2,4-diFPh 995 CH₂(2-MePr^(c)) Me CH₂OCOPh S2,4-diFPh 996 CH₂(2-MePr^(c)) Me CH₂OCOPh NH 2,4-diFPh 997 CH₂CH═CH₂ MeCH₂OCOPh S 2-ClPh 998 CH₂(2-MePr^(c)) Me CH₂OCOPh S 2-ClPh 999 CH₂CH═CH₂Me CH₂OCOPh S 4-ClPh 1000 CH₂Pr^(c) Me CH₂OCOPh S 4-ClPh 1001CH₂(2-MePr^(c)) Me CH₂OCOPh S 4-ClPh 1002 CH₂(2-MePr^(c)) Me CH₂OCOPh NH4-ClPh 1003 CH₂CH═CH₂ Me CH₂OCOPh S 2,4-diClPh 1004 CH₂Pr^(c) MeCH₂OCOPh S 2,4-diClPh 1005 CH₂(2-MePr^(c)) Me CH₂OCOPh S 2,4-diClPh 1006CH₂(2-MePr^(c)) Me CH₂OCOPh NH 2,4-diClPh 1007 CH₂(2-MePr^(c)) MeCH₂OCO₂Me S Ph 1008 CH₂CH═CH₂ Me CH₂OCO₂Me S 2-FPh 1009 CH₂(2-MePr^(c))Me CH₂OCO₂Me S 2-FPh 1010 CH₂CH═CH₂ Me CH₂OCO₂Me S 4-FPh 1011 CH₂CH═CH₂Me CH₂OCO₂Me NH 4-FPh 1012 CH₂CH═CHCH₃ Me CH₂OCO₂Me S 4-FPh 1013CH₂Pr^(c) Me CH₂OCO₂Me S 4-FPh 1014 CH₂(2-MePr^(c)) Me CH₂OCO₂Me S 4-FPh1015 CH₂(2-MePr^(c)) Me CH₂OCO₂Me NH 4-FPh 1016 CH₂CH═CH₂ Me CH₂OCO₂Me S2,4-diFPh 1017 CH₂Pr^(c) Me CH₂OCO₂Me S 2,4-diFPh 1018 CH₂(2-MePr^(c))Me CH₂OCO₂Me S 2,4-diFPh 1019 CH₂(2-MePr^(c)) Me CH₂OCO₂Me NH 2,4-diFPh1020 CH₂CH═CH₂ Me CH₂OCO₂Me S 2-ClPh 1021 CH₂(2-MePr^(c)) Me CH₂OCO₂Me S2-ClPh 1022 CH₂CH═CH₂ Me CH₂OCO₂Me S 4-ClPh 1023 CH₂Pr^(c) Me CH₂OCO₂MeS 4-ClPh 1024 CH₂(2-MePr^(c)) Me CH₂OCO₂Me S 4-ClPh 1025 CH₂(2-MePr^(c))Me CH₂OCO₂Me NH 4-ClPh 1026 CH₂CH═CH₂ Me CH₂OCO₂Me S 2,4-diClPh 1027CH₂Pr^(c) Me CH₂OCO₂Me S 2,4-diClPh 1028 CH₂(2-MePr^(c)) Me CH_(2OCO)₂Me S 2,4-diClPh 1029 CH₂(2-MePr^(c)) Me CH₂OCO₂Me NH 2,4-diClPh 1030CH₂(2-MePr^(c)) Me CH₂OCO₂Et S Ph 1031 CH₂CH═CH₂ Me CH₂OCO₂Et S 2-FPh1032 CH₂(2-MePr^(c)) Me CH₂OCO₂Et S 2-FPh 1033 CH₂CH═CH₂ Me CH₂OCO₂Et S4-FPh 1034 CH₂CH═CH₂ Me CH₂OCO₂Et NH 4-FPh 1035 CH₂CH═CHCH₃ Me CH₂OCO₂EtS 4-FPh 1036 CH₂Pr^(c) Me CH₂OCO₂Et S 4-FPh 1037 CH₂(2-MePr^(c)) MeCH₂OCO₂Et S 4-FPh 1038 CH₂(2-MePr^(c)) Me CH₂OCO₂Et NH 4-FPh 1039CH₂CH═CH₂ Me CH₂OCO₂Et S 2,4-diFPh 1040 CH₂Pr^(c) Me CH₂OCO₂Et S2,4-diFPh 1041 CH₂(2-MePr^(c)) Me CH₂OCO₂Et S 2,4-diFPh 1042CH₂(2-MePr^(c)) Me CH₂OCO₂Et NH 2,4-diFPh 1043 CH₂CH═CH₂ Me CH₂OCO₂Et S2-ClPh 1044 CH₂(2-MePr^(c)) Me CH₂OCO₂Et S 2-ClPh 1045 CH₂CH═CH₂ MeCH₂OCO₂Et S 4-ClPh 1046 CH₂Pr^(c) Me CH₂OCO₂Et S 4-ClPh 1047CH₂(2-MePr^(c)) Me CH₂OCO₂Et S 4-ClPh 1048 CH₂(2-MePr^(c)) Me CH₂OCO₂EtNH 4-ClPh 1049 CH₂CH═CH₂ Me CH₂OCO₂Et S 2,4-diClPh 1050 CH₂Pr^(c) MeCH₂OCO₂Et S 2,4-diClPh 1051 CH₂(2-MePr^(c)) Me CH₂OCO₂Et S 2,4-diClPh1052 CH₂(2-MePr^(c)) Me CH₂OCO₂Et NH 2,4-diClPh 1053 CH₂(2-MePr^(c)) MeCH₂OCO₂Pr S Ph 1054 CH₂(2-MePr^(c)) Me CH₂OCO₂Pr S 2-FPh 1055 CH₂CH═CH₂Me CH₂OCO₂Pr S 4-FPh 1056 CH₂Pr^(c) Me CH₂OCO₂Pr S 4-FPh 1057CH₂(2-MePr^(c)) Me CH₂OCO₂Pr S 4-FPh 1058 CH₂(2-MePr^(c)) Me CH₂OCO₂PrNH 4-FPh 1059 CH₂CH═CH₂ Me CH₂OCO₂Pr S 2,4-diFPh 1060 CH₂(2-MePr^(c)) MeCH₂OCO₂Pr S 2,4-diFPh 1061 CH₂(2-MePr^(c)) Me CH₂OCO₂Pr NH 2,4-diFPh1062 CH₂(2-MePr^(c)) Me CH₂OCO₂Pr S 2-ClPh 1063 CH₂CH═CH₂ Me CH₂OCO₂Pr S4-ClPh 1064 CH₂(2-MePr^(c)) Me CH₂OCO₂Pr S 4-ClPh 1065 CH₂CH═CH₂ MeCH₂OCO₂Pr S 2,4-diClPh 1066 CH₂(2-MePr^(c)) Me CH₂OCO₂Pr S 2,4-diClPh1067 CH₂(2-MePr^(c)) Me CH₂OCO₂Pr NH 2,4-diClPh 1068 CH₂(2-MePr^(c)) MeCH₂OCO₂Bu S Ph 1069 CH₂(2-MePr^(c)) Me CH₂OCO₂Bu S 2-FPh 1070 CH₂CH═CH₂Me CH₂OCO₂Bu S 4-FPh 1071 CH₂Pr^(c) Me CH₂OCO₂Bu S 4-FPh 1072CH₂(2-MePr^(c)) Me CH₂OCO₂Bu S 4-FPh 1073 CH₂(2-MePr^(c)) Me CH₂OCO₂BuNH 4-FPh 1074 CH₂CH═CH₂ Me CH₂OCO₂Bu S 2,4-diFPh 1075 CH₂(2-MePr^(c)) MeCH₂OCO₂Bu S 2,4-diFPh 1076 CH₂(2-MePr^(c)) Me CH₂OCO₂Bu NH 2,4-diFPh1077 CH₂(2-MePr^(c)) Me CH₂OCO₂Bu S 2-ClPh 1078 CH₂CH═CH₂ Me CH₂OCO₂Bu S4-ClPh 1079 CH₂(2-MePr^(c)) Me CH₂OCO₂Bu S 4-ClPh 1080 CH₂CH═CH₂ MeCH₂OCO₂Bu S 2,4-diClPh 1081 CH₂(2-MePr^(c)) Me CH₂OCO₂Bu S 2,4-diClPh1082 CH₂(2-MePr^(c)) Me CH₂OCO₂Bu NH 2,4-diClPh 1083 CH₂(2-MePr^(c)) MeCHO S Ph 1084 CH₂CH═CH₂ Me CHO S 2-FPh 1085 CH₂(2-MePr^(c)) Me CHO S2-FPh 1086 CH₂CH═CH₂ Me CHO S 4-FPh 1087 CH₂CH═CH₂ Me CHO NH 4-FPh 1088CH₂CH═CHCH₃ Me CHO S 4-FPh 1089 CH₂Pr^(c) Me CHO S 4-FPh 1090CH₂(2-MePr^(c)) Me CHO S 4-FPh 1091 CH₂(2-MePr^(c)) Me CHO NH 4-FPh 1092CH₂CH═CH₂ Me CHO S 2,4-diFPh 1093 CH₂Pr^(c) Me CHO S 2,4-diFPh 1094CH₂(2-MePr^(c)) Me CHO S 2,4-diFPh 1095 CH₂(2-MePr^(c)) Me CHO NH2,4-diFPh 1096 CH₂CH═CH₂ Me CHO S 2-ClPh 1097 CH₂(2-MePr^(c)) Me CHO S2-ClPh 1098 CH₂CH═CH₂ Me CHO S 4-ClPh 1099 CH₂Pr^(c) Me CHO S 4-ClPh1100 CH₂(2-MePr^(c)) Me CHO S 4-ClPh 1101 CH₂(2-MePr^(c)) Me CHO NH4-ClPh 1102 CH₂CH═CH₂ Me CHO S 2,4-diClPh 1103 CH₂Pr^(c) Me CHO S2,4-diClPh 1104 CH₂(2-MePr^(c)) Me CHO S 2,4-diClPh 1105 CH₂(2-MePr^(c))Me CHO NH 2,4-diClPh 1106 CH₂(2-MePr^(c)) Me CO₂H S Ph 1107 CH₂CH═CH₂ MeCO₂H S 2-FPh 1108 CH₂(2-MePr^(c)) Me CO₂H S 2-FPh 1109 CH₂CH═CH₂ Me CO₂HS 4-FPh 1110 CH₂CH═CH₂ Me CO₂H NH 4-FPh 1111 CH₂CH═CHCH₃ Me CO₂H S 4-FPh1112 CH₂Pr^(c) Me CO₂H S 4-FPh 1113 CH₂(2-MePr^(c)) Me CO₂H S 4-FPh 1114CH₂(2-MePr^(c)) Me CO₂H NH 4-FPh 1115 CH₂CH═CH₂ Me CO₂H S 2,4-diFPh 1116CH₂Pr^(c) Me CO₂H S 2,4-diFPh 1117 CH₂(2-MePr^(c)) Me CO₂H S 2,4-diFPh1118 CH₂(2-MePr^(c)) Me CO₂H NH 2,4-diFPh 1119 CH₂CH═CH₂ Me CO₂H S2-ClPh 1120 CH₂(2-MePr^(c)) Me CO₂H S 2-ClPh 1121 CH₂CH═CH₂ Me CO₂H S4-ClPh 1122 CH₂Pr^(c) Me CO₂H S 4-ClPh 1123 CH₂(2-MePr^(c)) Me CO₂H S4-ClPh 1124 CH₂(2-MePr^(c)) Me CO₂H NH 4-ClPh 1125 CH₂CH═CH₂ Me CO₂H S2,4-diClPh 1126 CH₂Pr^(c) Me CO₂H S 2,4-diClPh 1127 CH₂(2-MePr^(c)) MeCO₂H S 2,4-diClPh 1128 CH₂(2-MePr^(c)) Me CO₂H NH 2,4-diClPh 1129CH₂(2-MePr^(c)) Me CO₂Me S Ph 1130 CH₂(2-MePr^(c)) Me CO₂Me S 2-FPh 1131CH₂CH═CH₂ Me CO₂Me S 4-FPh 1132 CH₂Pr^(c) Me CO₂Me S 4-FPh 1133CH₂(2-MePr^(c)) Me CO₂Me S 4-FPh 1134 CH₂(2-MePr^(c)) Me CO₂Me NH 4-FPh1135 CH₂CH═CH₂ Me CO₂Me S 2,4-diFPh 1136 CH₂(2-MePr^(c)) Me CO₂Me S2,4-diFPh 1137 CH₂(2-MePr^(c)) Me CO₂Me NH 2,4-diFPh 1138CH₂(2-MePr^(c)) Me CO₂Me S 2-ClPh 1139 CH₂CH═CH₂ Me CO₂Me S 4-ClPh 1140CH₂(2-MePr^(c)) Me CO₂Me S 4-ClPh 1141 CH₂CH═CH₂ Me CO₂Me S 2,4-diClPh1142 CH₂(2-MePr^(c)) Me CO₂Me S 2,4-diClPh 1143 CH₂(2-MePr^(c)) Me CO₂MeNH 2,4-diClPh 1144 CH₂(2-MePr^(c)) Me CO₂Et S Ph 1145 CH₂(2-MePr^(c)) MeCO₂Et S 2-FPh 1146 CH₂CH═CH₂ Me CO₂Et S 4-FPh 1147 CH₂Pr^(c) Me CO₂Et S4-FPh 1148 CH₂(2-MePr^(c)) Me CO₂Et S 4-FPh 1149 CH₂(2-MePr^(c)) MeCO₂Et NH 4-FPh 1150 CH₂CH═CH₂ Me CO₂Et S 2,4-diFPh 1151 CH₂(2-MePr^(c))Me CO₂Et S 2,4-diFPh 1152 CH₂(2-MePr^(c)) Me CO₂Et NH 2,4-diFPh 1153CH₂(2-MePr^(c)) Me CO₂Et S 2-ClPh 1154 CH₂CH═CH₂ Me CO₂Et S 4-ClPh 1155CH₂(2-MePr^(c)) Me CO₂Et S 4-ClPh 1156 CH₂CH═CH₂ Me CO₂Et S 2,4-diClPh1157 CH₂(2-MePr^(c)) Me CO₂Et S 2,4-diClPh 1158 CH₂(2-MePr^(c)) Me CO₂EtNH 2,4-diClPh 1159 CH₂(2-MePr^(c)) Me CO₂Pr S 4-FPh 1160 CH₂(2-MePr^(c))Me CO₂Bu S 4-FPh 1161 CH₂(2-MePr^(c)) Me CO₂Ph S 4-FPh 1162 CH₂CH═CH₂ MeCH₂OH O 2,6-diFPh 1163 CH₂CH═CHCH₃ Me CH₂OH O 2,6-diFPh 1164 CH₂Pr^(c)Me CH₂OH O 2,6-diFPh 1165 CH₂(2-MePr^(c)) Me CH₂OH O 2,6-diFPh 1166CH₂CH═CH₂ Me CH₂OH O 2,6-diClPh 1167 CH₂CH═CHCH₃ Me CH₂OH O 2,6-diClPh1168 CH₂Pr^(c) Me CH₂OH O 2,6-diClPh 1169 CH₂(2-MePr^(c)) Me CH₂OH O2,6-diClPh 1170 CH₂CH═CH₂ Me CH₂OAc O 2,6-diFPh 1171 CH₂CH═CHCH₃ MeCH₂OAc O 2,6-diFPh 1172 CH₂Pr^(c) Me CH₂OAc O 2,6-diFPh 1173CH₂(2-MePr^(c)) Me CH₂OAc O 2,6-diFPh 1174 CH₂CH═CH₂ Me CH₂OAc O2,6-diFPh 1175 CH₂CH═CHCH₃ Me CH₂OAc O 2,6-diClPh 1176 CH₂Pr^(c) MeCH₂OAc O 2,6-diClPh 1177 CH₂(2-MePr^(c)) Me CH₂OAc O 2,6-diClPh 1178CH₂CH═CH₂ Me CHO O 2,6-diFPh 1179 CH₂CH═CHCH₃ Me CHO O 2,6-diFPh 1180CH₂Pr^(c) Me CHO O 2,6-diFPh 1181 CH₂(2-MePr^(c)) Me CHO O 2,6-diFPh1182 CH₂CH═CH₂ Me CHO O 2,6-diClPh 1183 CH₂CH═CHCH₃ Me CHO O 2,6-diClPh1184 CH₂Pr^(c) Me CHO O 2,6-diClPh 1185 CH₂(2-MePr^(c)) Me CHO O2,6-diClPh 1186 CH₂CH═CH₂ Me CO₂H O 2,6-diFPh 1187 CH₂CH═CHCH₃ Me CO₂H O2,6-diFPh 1188 CH₂Pr^(c) Me CO₂H O 2,6-diFPh 1189 CH₂(2-MePr^(c)) MeCO₂H O 2,6-diFPh 1190 CH₂CH═CH₂ Me CO₂H O 2,6-diClPh 1191 CH₂CH═CHCH₃ MeCO₂H O 2,6-diClPh 1192 CH₂Pr^(c) Me CO₂H O 2,6-diClPh 1193CH₂(2-MePr^(c)) Me CO₂H O 2,6-diClPh 1194 CH₂CH═CH₂ Et CH₂OH O 2,6-diFPh1195 CH₂CH═CHCH₃ Et CH₂OH O 2,6-diFPh 1196 CH₂Pr^(c) Et CH₂OH O2,6-diFPh 1197 CH₂(2-MePr^(c)) Et CH₂OH O 2,6-diFPh 1198 CH₂CH═CH₂ EtCH₂OH O 2,6-diClPh 1199 CH₂CH═CHCH₃ Et CH₂OH O 2,6-diClPh 1200 CH₂Pr^(c)Et CH₂OH O 2,6-diClPh 1201 CH₂(2-MePr^(c)) Et CH₂OH O 2,6-diClPh 1202CH₂(2-MePr^(c)) Me CH₂OH S 2,6-diFPh 1203 CH₂(2-MePr^(c)) Me CH₂OH NH2,6-diFPh 1204 CH₂(2-MePr^(c)) Me CH₂OH S 2,6-diClPh 1205CH₂(2-MePr^(c)) Me CH₂OH NH 2,6-diClPh

Throughout the table 1 the following abbreviations are used with thefollowing meanings.

Exemp. Comp. No.: Exemplification compound number,

Ac: acetyl, Bu: butyl, BU^(c): cyclobutyl, Bur: butyryl,

Et: ethyl, Hx^(c): cyclohexyl, Me: methyl, Pn^(c): cyclopentyl

Ph: phenyl, Pr: propyl, Prp : propionyl, Pr^(c): cyclopropyl.

In Table 1, preferred compounds are the compounds of ExemplificationCompound numbers 2,4, 8, 9, 17, 19, 20, 21, 22, 24, 25, 26, 27, 28, 29,30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47,48, 49, 50, 51, 56, 59, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72,73, 82, 90, 93, 95, 105, 106, 114, 116, 120, 121, 129, 132, 134, 138,140, 142, 144, 146, 167, 178, 188, 192, 196, 200, 216, 225, 233, 237,241, 245, 264, 277, 286, 290, 294, 298, 306, 307, 310, 311, 317, 323,326, 329, 332, 345, 351, 357, 360, 363, 366, 373, 377, 381, 383, 385,387, 394, 411, 414, 415, 416, 417, 418, 419, 420,421, 422, 423, 424,425, 426, 427, 430, 433, 436, 439, 442, 449, 450, 451, 452, 453, 454,455, 456, 457, 458, 461, 467, 470, 473, 476, 478, 480, 481, 482, 483,484, 485, 486, 487, 488, 492, 494, 496, 498, 503, 504, 505, 506, 507,508, 512, 514, 516, 518, 539, 542, 548, 558, 562, 564, 566, 583, 585,589, 592, 594, 595, 596, 597, 598, 600, 602, 604, 606, 607, 608, 625,626, 627, 633, 634, 665, 666, 667, 668, 669, 670, 671, 672, 675, 676,681, 682, 683, 684, 685, 686, 702, 703, 704, 705, 706, 707, 723, 724,725, 726, 727, 728, 834, 846, 858, 862, 889, 901, 930, 939, 990, 1014,1018, 1072, 1090, 1094, 1113, 1117, 1133, 1136, 1148, 1149, 1159, 1163,1164, 1165, 1167, 1169, 1171, 1173, 1175, 1177, 1181, 1185, 1189 and1193.

More preferred compounds are the compounds of Exemplification Compoundnumbers 9, 19, 20, 22, 25, 32, 33, 40, 41, 43, 47, 48, 59, 61, 62, 63,64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 82, 93, 95, 105, 106, 114, 116,120, 121, 134, 138, 142, 146, 167, 178, 311, 317, 416, 417, 420, 421,427, 436, 439, 442, 450, 451, 454, 455, 461, 485, 506, 508, 589, 592,594, 595, 596, 602, 606, 625, 633, 665, 666, 681, 682, 834, 846, 889,1090, 1113, 1133, 1163, 1164, 1165, 1167, 1169, 1171, 1173, 1175 and1177.

Further more preferred compounds are the compounds of ExemplificationCompound numbers 9, 20, 22, 32, 33, 41, 43, 47, 48, 61, 63, 65, 69, 71,73, 95, 106, 121, 421, 427, 455, 589, 594, 602, 606, 625, 1165 and 1169.

Still more preferred compounds are the compounds of ExemplificationCompound numbers 22, 33, 43, 48, 106, 121, 421, 455 and 594.

Most preferred compounds are the compounds of:

Exemplification compound number 22:1-(2-butenyl)-7-(4-fluorobenzyloxy)-3-hydroxymethyl-2-methylpyrrolo[2,3-d]pyridazine,

Exemplification compound number 33:7-(4fluorobenzyloxy)-3-hydroxymethyl-2-methyl-1-(2-methylcyclopropylmethyl)pyrrolo[2,3-d]pyridazine,

Exemplification compound number 43:1-(2-butenyl)-7-(2,4difluorobenzyloxy)-3-hydroxymethyl-2-methylpyrrolo[2,3-d]pyridazine,

Exemplification compound number 48:7-(2,4-difluorobenzyloxy)-3-hydroxymethyl-2-methyl-1-(2-methylcyclopropylmethyl)pyrrolo[2,3-d]py-ridazine,

Exemplification compound number 106:3-acetoxymethyl-7-4fluorobenzyloxy)-2-methyl-1-(2-methylcyclopropylmethyl)pyrrolo[2,3-d]pyridazine,and

Exemplification compound number 121:3-acetoxymethyl-7-(2,4difluorobenzyloxy)-2-methyl-1-(2-methylcyclopropylmethyl)pyrrolo[2,3-d]pyridazine.

In addition, of the compounds described above,1-[(1S,2S)-2-methylcyclopropylmethyl] derivatives are preferredcompounds.

The pyrrolopyridazine compounds of formula (I) can be prepared accordingto the following method.

In the above reaction scheme R¹, R², R⁴ and A have the same meanings asdescribed above.

The step 1 is a process preparing a compound of formula (Ia) and isaccomplished by reaction of a compound of formula (II) with an oxidizingagent in an inert solvent.

The oxidizing agent employed is, for example, an oxidizing agent bywhich a methyl group can be converted into a hydroxymethyl group, suchas ammonium cerium (IV) nitrate, manganese (III) acetate or seleniumdioxide; preferably ammonium cerium (IV) nitrate. The amount of theoxidizing agent is from 1.5 to 10 (preferably 2 to 6) moles to one moleof the compound of formula (II).

The employed inert solvent is not particularly limited provided that ithas no adverse effect on the reaction and can dissolve the startingmaterials to a certain extent. Such a solvent is, for example, ahalogeno-hydrocarbon such as methylene chloride, chloroform, carbontetrachloride, dichloroethane, chlorobenzene, or dichlorobenzene; anether such as diethyl ether, diisopropyl ether, tetrahydrofuran,dioxane, dimethoxyethane, or diethylene glycol dimethyl ether; acarboxylic acid or a carboxylic acid anhydride such as acetic acid,acetic anhydride, propionic acid, or benzoic acid; water; or mixturesthereof; and is preferably a carboxylic acid, a carboxylic acidanhydride, a carboxylic acid containing water or a mixture of acarboxylic acid and a carboxylic acid anhydride; and is more preferablyacetic acid, acetic anhydride, acetic acid containing water or a mixtureof acetic acid and acetic anhydride.

The reaction temperature is usually from 0° C. to 150° C. (preferablyfrom room temperature to 100° C.). The reaction time varies depending onthe reaction temperature and other factors but it is from 30 minutes to20 hours (preferably from 1 hour to 10 hours).

When a carboxylic acid or a carboxylic acid anhydride is used as theinert solvent in the step 1, in certain cases a product esterified atthe hydroxymethyl group of compound (Ia) by the carboxylic acid can beobtained. The esterified compound is hydrolyzed according to aconventional method to give the compound of formula (Ia). For examplethe esterified compound is treated with a base (for example an alkalimetal hydroxide such as lithium hydroxide, sodium hydroxide, orpotassium hydroxide; or an alkali metal carbonate such as sodiumcarbonate, potassium carbonate; preferably an alkali metal hydroxide andmost preferably lithium hydroxide) at from 0° C. to 100° C. (preferablyfrom 10° C. to 50° C.) for from 10 minutes to 10 hours (preferably from20 minutes to 5 hours) in an inert solvent containing water (forexample, an alcohol containing water such as methanol containing wateror ethanol containing water) to give a compound of formula (Ia).

A compound of formula (Id), which is a compound of formula (I) whereinR³ is a C₂-C₆ aliphatic acyloxymethyl group, aC₆-C₁₀arylcarbonyloxymethyl group which may be optionally substitutedwith substituents selected from the group consisting of C₁-C₆ alkyl,C₁-C₆ alkoxy and halogeno, or a C₁-C₆ alkoxycarbonyloxymethyl group, canbe prepared by acylation of a compound of formula (Ia).

In the formula of (Id), R⁵ represents a C₂-C₆ aliphatic acyl group, aC₆-C₁₀ arylcarbonyl group which may be optionally substituted withsubstituents selected from the group consisting of C₁-C₆ alkyl, C₁-C₆alkoxy and halogeno, or a C₁-C₆ alkoxycarbonyl group, and R¹, R², R⁴ andA have the same meanings as described above.

The acylating reagent is, for example, a C₂-C₆ aliphatic acyl halidesuch as acetyl chloride, acetyl bromide, propionyl chloride, propionylbromide, butyryl chloride, isobutyryl chloride, valeryl chloride, orhexanoyl chloride; a C₂-C₆ aliphatic carboxylic acid anhydride such asacetic anhydride, propionic anhydride, or hexanoic anhydride; a C₆-C₁₀arylcarbonyl halide which may be optionally substituted withsubstituents selected from the group consisting of C₁-C₆ alkyl, C₁-C₆alkoxy and halogeno, such as benzoyl chloride, benzoyl bromide, toluoylchloride, toluoyl bromide, methoxybenzoyl chloride, chlorobenzoylchloride, fluorobenzoyl chloride, or naphthoyl chloride; or a C₁-C₆alkoxycarbonyl halide such as methoxycarbonyl chloride, ethoxycarbonylchloride, ethoxycarbonyl bromide, propoxycarbonyl chloride,butoxycarbonyl chloride, pentyloxycarbonyl chloride, or hexyloxycarbonylchloride; preferably a C₂-C₆ aliphatic acyl chloride, a C₆-C₁₀arylcarbonyl chloride which may be optionally substituted withsubstituents selected from the group consisting of C₁-C₆ alkyl C₁-C₆alkoxy and halogeno or a C₁-C₆ alkoxycarbonyl chloride.

The employed base is, for example, an alkali metal amide such as lithiumamide, sodium amide, or potassium amide; an alkali metal carbonate suchas lithium carbonate, sodium carbonate, or potassium carbonate; analkali metal alkoxide such as lithium methoxide, sodium methoxide,sodium ethoxide, or potassium t-butoxide; or an organic amine such astriethylamine, tributylamine, diisopropylethylamine, N-ethylmorpholine,pyridine, picoline, 4-(N,N-dimethylamino)pyridine, quinoline,N,N-dimethylaniline, N,N-diethylaniline,1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane(DABCO), or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); preferably anorganic amine and most preferably triethylamine or pyridine.

The employed inert solvent is not particularly limited provided that ithas no adverse effect on the reaction and can dissolve the startingmaterials to a certain extent. Such a solvent is, for example, anaromatic hydrocarbon such as benzene, toluene, or xylene; ahalogeno-hydrocarbon such as methylene chloride, chloroform, carbontetrachloride, dichloroethane, chlorobenzene, or dichlorobenzene; anether such as diethyl ether, diisopropyl ether, tetrahydrofuran,dioxane, dimethoxyethane, or diethylene glycol dimethyl ether-, ormixtures thereof; and is preferably a halogeno-hydrocarbon or an ether;and is more preferably methylene chloride, chloroform, diethyl ether ortetrahydrofuran.

The reaction temperature is usually from 0° C. to 100° C. (preferablyfrom 10° C. to 50° C.). The reaction time varies depending on thereaction temperature and other factors but it is from 10 minutes to 100hours (preferably from 30 minutes to 5 hours).

The step 2 is a process for preparing a compound of formula (Ib) and isaccomplished by reaction of a compound of formula (Ia) with an oxidizingagent in an inert solvent.

The employed oxidizing agent is, for example, an oxidizing agent bywhich a hydroxymethyl group can be converted into a formyl group, suchas manganese dioxide, pyridinium chlorochromate (PCC), pyridiniumdichromate (PDC), or a mixture of dimethyl sulfoxide and an acidanhydride (for example an aliphatic carboxylic acid anhydride which maybe optionally substituted with halogeno, such as acetic anhydride,trifluoroacetic anhydride, or propionic anhydride; preferably aceticanhydride or trifluoroacetic anhydride); preferably manganese dioxide.The amount of the oxidizing agent is usually from 1 to 50 (preferably 2to 30) moles to one mole of the compound of formula (Ia).

The employed inert solvent is not particularly limited provided that ithas no adverse effect on the reaction and can dissolve the startingmaterials to a certain extent. Such a solvent is, for example, anaromatic hydrocarbon such as benzene, toluene, or xylene; ahalogeno-hydrocarbon such as methylene chloride, chloroform, carbontetrachloride, dichloroethane, chlorobenzene, or dichlorobenzene; anether such as diethyl ether, diisopropyl ether, tetrahydrofuran,dioxane, dimethoxyethane, or diethylene glycol dimethyl ether; ormixtures thereof; and is preferably a halogeno-hydrocarbon; and is mostpreferably methylene chloride.

The reaction temperature is usually from 0° C. to 150° C. (preferablyfrom room temperature to 100° C.). The reaction time varies depending onthe reaction temperature and other factors but it is from 30 minutes to40 hours (preferably from 1 hour to 20 hours).

The step 3 is a process preparing a compound of formula (Ic) and isaccomplished by reaction of a compound of formula (Ib) with an oxidizingagent in an inert solvent.

The employed oxidizing agent is, for example, an oxidizing agent bywhich a formyl group can be converted into a carboxyl group, such assilver oxide, pyridinium chlorochromate (PCC), or pyridinium dichromate(PDC); preferably silver oxide. The amount of the oxidizing agent isusually from 1 to 20 (preferably 2 to 10) moles to one mole of thecompound of formula (Ib). When silver oxide is used as an oxidizingagent, silver oxide prepared by reaction of silver nitrate with analkali metal hydroxide (preferably sodium hydroxide) is preferably used.

The employed inert solvent is not particularly limited provided that ithas no adverse effect on the reaction and can dissolve the startingmaterials to a certain extent. Such a solvent is, for example, ahalogeno-hydrocarbon such as methylene chloride, chloroform, carbontetrachloride, dichloroethane, chlorobenzene, or dichlorobenzene; anether such as diethyl ether, diisopropyl ether, tetrahydrofuran,dioxane, dimethoxyethane, or diethylene glycol dimethyl ether; analcohol such as methanol, or ethanol; a carboxylic acid such as aceticacid, propionic acid, or benzoic acid; water; or mixtures thereof; andis preferably an alcohol, an alchohol containing water, a carboxylicacid, a carboxylic acid containing water or water; and is morepreferably an alcohol containing water; and is most preferably ethanolcontaining water.

The reaction temperature is usually from 0° C. to 150° C. (preferablyfrom room temperature to 100° C.). The reaction time varies depending onthe reaction temperature and other factors but it is from 1 hour to 72hours (preferably from 12 hours to 48 hours).

A compound of formula (Ie), which is a compound of formula (I) whereinR³ is a C₁-C₆ alkoxycarbonyl group or a C₆-C₁₀ aryloxycarbonyl groupwhich may be optionally substituted with substituents selected from thegroup consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy and halogeno, can beprepared by esterification of a compound of formula (Ic).

In the formula (Ie), R⁶ represents a C₁-C₆ alkyl group, or a C₆-C₁₀ arylgroup which may be optionally substituted with substituents selectedfrom the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy and halogeno andR¹, R², R⁴ and A have the same meanings as described above.

The esterification is accomplished by reaction of a compound of formula(Ic) with a halogenating agent in an inert solvent to afford acarboxylic acid halide, followed by reaction of the carboxylic acidhalide with an alcohol or a phenol derivative in the presence of a basein an inert solvent. The two step reactions can be carried out in asingle reaction vessel, wherein the compound of formula (Ic) is reactedwith a halogenating agent and, if necessary, the solvent can be removedfrom the reaction mixture.

The halogenating agent employed is, for example, a thionyl halide suchas thionyl chloride, thionyl bromide or a phosphorus halide such asphosphorus trichloride, phosphorus pentachloride, phosphorusoxychloride, or phosphorus oxybromide; preferably thionyl chloride orphosphorus oxychloride.

The inert solvent employed in the reaction of the compound of formula(Ic) with a halogenating agent is not particularly limited provided thatit has no adverse effect on the reaction and can dissolve the startingmaterials to a certain extent. Such a solvent is, for example, anaromatic hydrocarbon such as benzene, toluene, or xylene; ahalogeno-hydrocarbon such as methylene chloride, chloroform, carbontetrachloride, dichloroethane, chlorobenzene, or dichlorobenzene; anether such as diethyl ether, diisopropyl ether, tetrahydrofuran,dioxane, dimethoxyethane, or diethylene glycol dimethyl ether; ormixtures thereof; and is preferably an ether; and is most preferablydiethyl ether or tetrahydrofuran.

The reaction temperature is usually from 0° C. to 100° C. (preferably10° C. to 50° C.). The reaction time varies depending on the reactiontemperature and other factors but it is from 10 minutes to 10 hours(preferably from 30 minutes to 5 hours).

The inert solvent employed in the reaction of the carboxylic acid halidewith an alcohol or phenol derivative is the same solvent as described inthe reaction of the compound of formula (Ic) with a halogenating agent.The reaction temperature and the time required for the reaction are inthe same range as described in the reaction of the compound of formula(Ic) with a halogenating agent.

In each step described above each desired compound may be isolated byconventional procedures from the reaction mixture. For example, it maybe obtained 1) by filtration of the reaction mixture when insolublematerial exists in the reaction mixture, followed by evaporation of thesolvent of the filtrate; or by 1) concentration of the reaction mixture,2) addition of water to the residue followed by partition between waterand an appropriate organic solvent immiscible with water, 3) drying theextract over anhydrous magnesium sulfate and the like, followed by 4)concentration of the extract. The desired compound can be, if necessary,be further purified by conventional procedures such asrecrystallization, column chromatography and the like.

A compound of formula (I) can be transformed into a pharmaceuticallyacceptable salt thereof by treatment of the compound of formula (I) withan acid according to a conventional technique. For example the desiredsalt can be obtained by reaction of a compound of formula (I) with anacid in an inert solvent (preferably an ether such as diethyl ether,tetrahydrofuran, or dioxane; an alcohol such as methanol, ethanol, orpropanol; or a halogeno-hydrocarbon such as methylene chloride, orchloroform) at room temperature for from 5 minutes to 1 hour, followedby evaporation of the solvent.

The starting compound of formula (II) is known or can easily be preparedby the reaction of a pyrrole compound of formula (III) with a compoundof formula R¹-X (IV) according to a known method (for example JapanesePatent Application Publication Hei 7-247285);

wherein R⁷ represents a C₁-C₆ alkyl group, R² has the same meanings asdescribed above, X represents a halogen atom (preferably a chlorine orbromine atom), and R¹ has the same meanings as described above.

The compounds of formula (III) and (IV) are also known or can easily beobtained by a known procedure (for example Japanese Patent ApplicationPublication Hei 7-247825; Monatschefte fur Chemie (1973), 104, 925; J.Chem. Soc., Perkin.Trans.II (1979) 287 and the like).

In addition each desired optically active compound of formula (I) and(IV) (for example 1S,2S-form) can be obtained by optical resolution of aracemic form of the corresponding compound (a mixture of 1S,2S-form andIR,2R-form and the like). The optical resolution can be carried out byan appropriate selection from conventional techniques such aschromatography on a column for optical resolution, preferentialcrystallization, and resolution of a mixture of diastereomeric salts.

The compounds of formula (I) or pharmaceutically acceptable saltsthereof of this invention exhibit potent gastric acid secretioninhibition activity, gastric mucous membrane protection activity andpotent antibacterial activity against Helicobacter pylori and they haveexcellent properties as a medicament. The compounds of formula (I) orpharmaceutically acceptable salts thereof are useful as a prophylacticor therapeutic medicament for the prevention and treatment of ulcerativediseases such as peptic ulcer, acute or chronic gastric ulcer,gastrisis, reflux esophagitis, gastroesophageal reflux disorder,dyspepsia, gastric hyperacidity, Zollinger-Ellison syndrome etc. and forbacterial infections arising from Helicobacter pylori.

When used as a prophylactic or therapeutic medicament for the diseasesdescribed above, a compound of formula (I) or a pharmaceuticallyacceptable salt thereof (the active ingredient) can be administeredalone or can be presented as part of a pharmaceutical formulation. Thepharmaceutical formulation is prepared by blending the active ingredientwith appropriate pharmaceutically acceptable carriers, e.g., excipients,diluents and the like, followed by formulation in the form of tablets,capsules, granules, powders or syrups and the like for oraladministration or in the form of injections and the like for parenteraladministration (preferably oral administration).

The production of such pharmaceutical formulations is carried outaccording to general techniques known to those skilled in the art usingcarriers which may includes such additives as an excipient, a binder, adisintegrant, a lubricant, a stabilizer, a corrigent, a diluent and asolvent for injections.

The excipient is, for example, a sugar derivative such as lactose,sucrose, glucose, mannitol, or sorbitol; a starch derivative such ascorn starch, potato starch, α-starch, dextrin, or carboxymethyl starch;a cellulose derivative such as crystalline cellulose, low-substitutedhydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethylcellulose, calcium carboxymethyl cellulose, or internally bridged sodiumcarboxymethyl cellulose; acacia; dextran; pullulan; a silicatederivative such as light silicic acid anhydride, synthetic aluminiumsilicate, or magnesium aluminate meta-silicate; a phosphonate derivativesuch as calcium phosphonate; a carbonate derivative such as calciumcarbonate; a sulfate derivative such as calcium sulfate; and the like.

The binder is, for example, one of the excipients described above;gelatin; polyvinylpyrrolidone; macrogol (trade mark) and the like.

The disintegrant is, for example, one of the excipients described above;a chemically modified starch or cellulose derivative such as sodiumcroscarmellose or sodium carboxymethyl starch; bridgedpolyvinylpyrrolidone; and the like.

The lubricant is, for example, talc; stearic acid; a metal salt ofstearic acid such as calcium stearate, or magnesium stearate; colloidalsilica; a wax such as bee gum and spermaceti; boric acid; glycol; acarboxylic acid such as fumaric acid, or adipic acid; a sodiumcarboxylate such as sodium benzoate; a sulfate such as sodium sulfate;leucine; a laurylsulfate such as sodium laurylsulfate, or magnesiumlaurylsulfate; a silicic acid such as silicic acid anhydride, or asilicic acid hydrate; one of the starch derivatives described above inrelation to the excipients; and the like.

The stabilizer is, for example, a p-hydroxybenzoate derivative such asmethylparaben, or propylparaben; an alcohol such as chlorobutanol,benzyl alcohol, or phenylethyl alcohol; benzalkonium chloride; a phenolderivative such as phenol, or cresol; thimerosal; dehydroacetic acid;sorbic acid; and the like.

The corrigent is, for example, a sweetening, souring, or flavoringagent, which are conventionally used; and the like.

The solvent for injection is, for example, water, ethanol, glycerin andthe like.

Suitable dosage levels will depend on the condition of the patient,human or other animal, the disease, whether the drug administration isfor prevention or treatment, the age of the patient and the like, buttypically suitable dosage levels for an active ingredient of the presentinvention are from 1 mg (preferably 5 mg) to 1000 mg (preferably 500 mg)for oral administration and from 0.1 mg (preferably 1 mg) to 500 mg(preferably 300 mg) for intravenous administration per unit dose, perday, for an adult human, respectively. The dosages described above arepreferably administered from one time to six times throughout the day,depending on the condition of the disease.

The following Examples, Reference Examples, Test Examples andFormulation Examples are intended to further illustrate the presentinvention and are not intended to limit the scope of the invention.

EXAMPLE 13-Acetoxymethyl-7-(4-fluorobenzyloxy)-2-methyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d]-pyridazine

To a solution of7-(4-fluorobenzyloxy)-2,3-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d]pyridazine(0.679 g, 2.00 mmol) in acetic acid (40 ml) was added ammonium cerium(IV) nitrate (6.58 g, 12.0 mmol) at room temperature. The mixture wasstirred at 60° C. for 3 hours, poured into water and extracted withethyl acetate. The extract was washed with a saturated aqueous sodiumchloride solution, dried over anhydrous magnesium sulfate andconcentrated in vacuo. The residue was chromatographed on a silica gelcolumn using hexane/ethyl acetate=1/1 as the eluant to afford an oilwhich was crystallized in hexane to give the title compound (0.255 g,28%) as pale yellow crystals.

Melting point: 122-123° C. Mass spectrum (CI, m/z): 398 (M⁺+1). NMRspectrum CDCl₃, δppm): 0.13-0.20 (m, 1H), 0.37-0.44 (m, 1H), 0.61-0.68(m, 1H), 0.84-0.91 (m, 1H), 0.90 (d; J=5.9 Hz, 3H), 2.05 (s, 3H), 2.48(s, 3H), 4.14 (dd; J=14.6 Hz, 7.3 Hz, 1H), 4.31 (dd; J=14.6 Hz, 6.3 Hz,1H), 5.27 (s, 2H), 5.65 J=12.0 Hz, 1H), 5.70 (d; J=12.0 Hz, 1H),7.05-7.12 (m, 2H), 7.48-7.53 (m,2H), 9.12 (s, 1H).

EXAMPLE 2

7-(4-Fluorobenzyloxy)-3-hydroxymethyl-2-methyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d]-pyridazine

To a solution of7-(4-fluorobenzyloxy)-2,3-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3d]pyridazine(67.9 g, 200 mmol) in acetic acid (800 ml) was added ammonium cerium(IV) nitrate (329 g, 600 mmol) at room temperature. The mixture wasstirred at 55° C. for 8 hours, poured into water and extracted withethyl acetate. The extract was washed with a saturated aqueous sodiumchloride solution, dried over anhydrous magnesium sulfate andconcentrated in vacuo. To the residue were added methanol (500 ml) and a2N aqueous lithium hydroxide solution (160 ml) and the mixture wasstirred at room temperature for 40 minutes. The reaction mixture wasneutralized with 1N hydrochloric acid and the methanol was evaporatedoff in vacuo. The resulting mixture was extracted with chloroform. Theextract was washed with a saturated aqueous sodium chloride solution,dried over anhydrous magnesium sulfate and concentrated in vacuo. Theresidue was chromatographed on a silica gel column using ethyl acetateand ethyl acetate/methanol=9/1 as the eluant to afford crystals whichwere washed with ethyl acetate to give the title compound (24.6 g, 35%)as pale yellow crystals.

Melting point: 128-129° C. Mass spectrum (CI, m/z): 356 (M⁺+1). NMRspectrum CDCl₃, δppm): 0.10-0.16 (m, 1H), 0.340.40 (m, 1H), 0.58-0.68(m, 1H), 0.77-0.86 (m, 1H), 0.87 (d; J=5.9 Hz, 3H), 2.44 (s, 3H), 4.09(dd; J=14.6 Hz, 7.3 Hz, 1H), 4.26 (dd; J=14.6 Hz, 6.3 Hz, 1H), 4.82 (s,2H), 5.57 (d; J=11.7 Hz, 1H), 5.62 (d; J=11.7 Hz, 1H), 7.04-7.09 (m,2H), 7.47 (dd; J=8.8 Hz, 5.4 Hz, 2H), 9.07 (s, 1H). Optical rotation:[α]_(D) ²⁰ =+18.2°(C=1.00, MeOH).

EXAMPLE 37-(4-Fluorobenzyloxy)-3-formyl-2-methyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d]pyridazine

To a solution of7-(4-fluorobenzyloxy)-3-hydroxymethyl-2-methyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d]pyridazine(64.3 g, 181 mmol) in methylene chloride (900 ml) was added activatedmanganese dioxide (472 g, 5.43 mol) at room temperature. The mixture wasstirred at room temperature for 18 hours. The reaction mixture wasfiltered through celite (trade mark) and the filtrate was concentratedin vacuo. The crude crystals (45.7 g) were washed with ethyl acetate andhexane to give the title compound (44.3 g, 69%) as pale yellow crystals.

Melting point: 138.5-139.5° C. Mass spectrum (CI, m/z): 354 (M⁺+1). NMRspectrum (CDCl₃, δppm): 0.19-0.26 (m, 1H), 0.40-0.47 (m, 1H), 0.71-0.78(m, 1H), 0.84-0.91 (m, 1H), 0.92 (d; J=5.9 Hz, 3H), 2.75 (s, 3H), 4.19(dd; J=14.6 Hz, 7.1 Hz, 1H), 4.35 (dd; J=14.6 Hz, 6.6 Hz, 1H), 5.67 (d;J=12.0 Hz, 1H), 5.73 (d; J=12.0 Hz, 1H), 7.07-7.14 (m, 2H), 7.51 (dd;J=8.5 Hz, 5.4 Hz, 2H), 9.63 (s, 1H), 10.22 (s, 1H).

Optical rotation: [α]_(D) ²⁰=+20.4° (C=1.00, MeOH).

EXAMPLE 43-Carboxy-7-(4-fluorobenzyloxy)-2-methyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2.3-d]pyridazine

To a solution of silver nitrate (0.85 g, 5 mmol) in water (2.5 ml) wasadded an aqueous 2N lithium hydroxide solution (3 ml), followed by asolution of7-(4-fluorobenzyloxy)-3-formyl-2-methyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d]pyridazine(0.177 g, 0.5 mmol) in ethanol (10 ml). The mixture was stirred at roomtemperature for 48 hours. To the reaction mixture was added 1Nhydrochloric acid (3 ml) and the resulting mixture was filtered throughcelite (trade mark). The celite (trade mark) was washed with ethanol (30ml). To the combined filtrates was added water and the resulting mixturewas extracted with chloroform. The extract was dried over anhydrousmagnesium sulfate and concentrated in vacuo. The residue waschromatographed on a silica gel column using chloroform/isopropanol=19/1as the eluant to give the title compound (0.094 g, 51%) as pale yellowcrystals.

Melting point: 170-225° C. Mass spectrum (CI, m/z): 370 (M⁺+1). NMRspectrum CDCl₃, δppm): 0.20-0.25 (m, 1H), 0.40-0.46 (m, 1H), 0.63-0.69(m, 1H), 0.86-0.92 (m, 1H), 0.91 (d; J=5.9 Hz, 3H), 2.86 (s, 3H), 3.60(bs, 1H), 4.26 (dd; J=14.7 Hz, 7.3 Hz, 1H), 4.40 (dd; J=14.7 Hz, 6.8 Hz,1H), 5.67 (d; J=11.7 Hz, 1H), 5.72 (d; J=11.7 Hz, 1H), 7.08-7.14 (m,2H), 7.53 (dd; J=8.8 Hz, 5.4 Hz, 2H), 9.88 (bs, 1H). Optical rotation:[α]_(D) ²⁰=+15.8° (C=1.00, MeOH),

Reference Example 17-(4-Fluorobenzyloxy)-2,3-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-]-pyridazine

(a) Methyl3-formyl-4,5-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrole-2-carboxylate

Potassium tert-butoxide (3.49 g, 35.1 mmol) was added to a solution ofmethyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate (5.79 g, 31.9 mmol)and 18-crown-6 (0.41 g, 1.55 mmol) in tetrahydrofuran (130 ml) and themixture was stirred at room temperature for 1 hour. After dropwiseaddition over 30 minutes of (1S,2S)-2-methylcyclopropylmethyl bromide(5.71 g, 38.3 mmol) to the reaction mixture at 50° C., the mixture washeated under reflux for 3 hours. Potassium tert-butoxide (0.36 g, 3.22mmol) and (1S,2S)-2-methylcyclopropylmethyl bromide (0.48 g, 3.21 mmol)were further added to the mixture and this mixture was heated for 1hour. The reaction mixture was poured into ice-water and extracted withethyl acetate. The extract was washed with water and a saturated aqueoussodium chloride solution and then dried over anhydrous magnesiumsulfate. The solvent was removed in vacuo to afford the desired compound(8.26 g, 100%) as a pale brown oil.

Mass spectrum (CI, m/z): 250 (M⁺+1) NMR spectrum CDCl₃, δppm): 0.25 (dt;J=8 Hz, 5 Hz, 1H), 0.48 (dt; J=8 Hz, 5 Hz 1H), 0.71-0.80 (m, 1H),0.82-0.89 (m, 1H), 1.00 (d; J=6 Hz, 3H), 2.20 (s, 3H), 3.89 (s, 3H),4.25 (d; J=7 Hz, 2H), 10.43 (s, 1H). Optical rotation: [α]_(D) ²⁰=+17.6°(C=1.02, EtOH).

(b)2,3-Dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]-6,7-dihydropyrrolo[2,3-d]pyridazine-7-one

Hydrazine hydrate (1.92 g, 38.4 mmol) was added to a solution of methyl3-formyl-4,5-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrole-2-carboxylate(7.96 g 31.9 mmol) in acetic acid (38 ml) at room temperature and themixture was stirred at 90° C. for 1 hour. After the reaction wascompleted, the reaction mixture was cooled to room temperature andpoured into ice-water. The crude crystals were collected by filtration,washed with water and dissolved in a mixture of chloroform and methanol(9:1). The organic layer was separated, washed with a saturated aqueoussodium chloride solution and then dried over anhydrous magnesiumsulfate. The solvent was removed in vacuo and to the residue was added amixture of toluene and hexane. The precipitate was collected byfiltration to afford the desired compound (7.02 g, 95.0%) as a paleyellowish white powder.

Mass spectrum (CI, m/z): 232 (M⁺+1) NMR spectrum (CDCl₃, δppm): 0.22(dt; J=8 Hz, 5 Hz, 1H), 0.64 (dt; J=8 Hz, 5 Hz, 1H), 0.86-0.95 (m, 2H),0.98 (d; J=5 Hz, 3H), 2.21 (s, 3H), 2.35 (s, 3H), 4.44(d; J=7 Hz, 2Hl),8.05 (s, 1H), 9.97 (s, 1H). Optical rotation: [α]_(D) ²⁰=+11.2° (C=0.50,EtOH).

(c)7-Chloro-2,3-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d]pyridazine

Phosphorus oxychloride (55 ml, 590 mmol) was added to2,3-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]-6,7-dihydropyrrolo[2,3-d]pyridazine-7-one(6.95 g, 30.1 mmol) and the mixture was stirred at 90° C. for 3.5 hours.After the reaction was completed, the reaction mixture was cooled toroom temperature and poured into ice-water. The aqueous solution wasneutralized with a 5N aqueous sodium hydroxide solution and extractedwith methylene chloride. The extract was washed with water, dried overanhydrous magnesium sulfate and then concentrated in vacuo. Hexane wasadded to the residue and the precipitate was collected by filtration toafford the desired compound (6.90 g, 92.0%) as a pale yellow powder.

Mass spectrum (CI, m/z): 250 (M⁺+1) NMR spectrum CDCl₃, δppm): 0.29 (dt;J=8 Hz, 5 Hz, 1H), 0.54 (dt; J=8 Hz, 5 Hz, 1H), 0.73-1.02 (m, 5H), 2.30(s, 3H), 2.43 (s, 3H), 4.44 (d; J=6 Hz, 2H), 9.15 (s,1H). Opticalrotation: [α]_(D) ²⁰+12.3° (C=1.01, EtOH).

(d)7-(4-Fluorobenzyloxy)-2,3-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d]-pyridazine

A solution of p-fluorobenzyl alcohol (1.45 g, 11.5 mmol) intetrahydrofuran (2 ml) was added dropwise to a solution of sodiumhydride (0.26 g, 10.8 mmol) in tetrahydrofuran (6 ml) and the mixturewas stirred at room temperature for 30 minutes. A solution of7-chloro-2,3-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d]pyridazine(2.50 g, 10.0 mmol) in tetrahydrofuran (13 ml) was added dropwise to thereaction mixture at room temperature and the mixture was heated underreflux for 3 hours. After the reaction was completed, the reactionmixture was poured into ice-water and extracted with ethyl acetate. Theextract was washed with a saturated aqueous sodium chloride solution,dried over anhydrous magnesium sulfate and then concentrated in vacuo.Hexane was added to the concentrated solution, and the precipitate wascollected by filtration and then recrystallized from a mixture of ethylacetate and hexane to afford the title compound (2.25 g, 66.4%) as palebrown crystals.

Mp: 114-115° C. Mass spectrum (CI, m/z): 340 (M⁺+1) 1H-NMR spectrum(CDCl₃, δppm): 0.14 (dt; J=8 Hz, 5 Hz, 1H), 0.39 (dt; J=8 Hz, 5 Hz, 1H),0.59-0.65 (m, 1H), 0.76-0.85 (m, 1H), 0.89 (d; J=6 Hz, 3H), 2.26 (s,3H),2.36 (s, 3H), 4.13 (dd; J=15 Hz, 7 Hz, 1H), 4.27 (dd; J=15 Hz, 6 Hz,1H), J=12 Hz, 1H), 5.68 (d; J=12 Hz, 1H), 7.05-7.12 (m, 2H), 7.47-7.52(m, 2H), 8.96 (s, 1H). Optical rotation: [α]_(D) ²⁰=+17.9° (C=0.50,EtOH).

Reference Example 2 Methyl3-formyl-4,5-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrole-2-carboxylate

(a)Methyl-4,5-dimethyl-1-[(E)-2-methylcyclopropylmethyl]pyrrole-2-carboxylate

Potassium tert-butoxide (18.33 g, 164 mmol) was added to a solution ofmethyl 4,5-dimethylpyrrole-2-carboxylate (25.02 g, 163 mmol) and18-crown-6 (3.19 g, 12.1 mmol) in tetrahydrofuran (150 ml) and themixture was stirred at room temperature for 1 hour. To this mixture wasadded a solution of (E)-2-methylcyclopropylmethyl bromide (racemate,12.70 g, 85.2 mmol) and the mixture was heated under reflux for 7 hours.After the reaction was completed, the reaction mixture was poured intoice-water and extracted with ethyl acetate. The extract was washed withwater and a saturated aqueous sodium chloride solution, dried overanhydrous magnesium sulfate and then concentrated in vacuo. The residuewas chromatographed on a column using toluene as the eluant to affordthe desired compound (racemate, 13.50 g, 71.6%) as a brown oil.

Mass spectrum (CI, m/z): 222 (M⁺+1) NMR spectrum (CDCl₃, δppm): 0.20(dt; J=8 Hz, 5 Hz, 1H), 0.48 (dt; J=8 Hz, 5 Hz, 1H), 0.67-0.93 (m, 2H),0.98 (d; J=6 Hz, 3H), 2.01 (s, 3H), 2.18 (s, 3H), 3.76 (s,3H) 4.21 (d;J=7 Hz, 2H), 6.76 (s, 1H).

(b) Methyl4,5-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrole-2-carboxylate

Methyl4,5-dimethyl-1-[(E)-2-methylcyclopropylmethyl]pyrrole-2-carboxylate(10.00 g) was chromatographed by high pressure liquid chromatography toafford the title [(S,S) form] compound (3.33 g) and the [(R,R) form]compound (3.97 g), which is the antipode of the [(S,S) form] compound.

Separation conditions;

Column: CHIRALCEL OJ, 50Φ×500 mm, Daicel Chemical Industries, Ltd.

Eluant: hexane/2-propanol=1000/1

Flow rate: 25 ml per minute

The title [(S,S) form] compound:

Mass spectrum (CI, m/z): 222 (M⁺+1) NMR spectrum CDCl₃, δppm): 0.20 (dt;J=8 Hz, 5 Hz, 1H), 0.48 (dt; J=8 Hz, 5 Hz, 1H), 0.66-0.80 (m, 1H),0.82-0.91 (m, 1H), 0.98 (d; J=6 Hz, 3H), 2.01 (s, 3H), 3.76 (s, 3H),4.21 (d; J=7 Hz, 2H), 6.76 (s, 1H). Optical rotation: [α]_(D) ²⁰=+17.6°(C=1.00, EtOH).

The antipode [(R,R) form] compound: Mass spectrum (CI, m/z): 222 (M⁺+1)NMR spectrum (CDCl₃, δppm): 0.20 (dt; J=8 Hz, 5 Hz, 1H), 0.48 (dt; J=8Hz, 5 Hz, 1H), 0.66-0.80 (m, 1H), 0.82-0.91 (m, 1H), 0.98 (d; J=6 Hz,3H), 2.01 (s,3H),2.18 (s, 3H), 3.77 (s, 3H), 4.21 (d; J=7 Hz, 2H), 6.76(s, 1H). Optical rotation: [α]_(D) ²⁰=−17.0° (C=1.01, EtOH).

(c) Methyl 3-formyl-4,5-dimethyl-1-[(1S2S)-2-methylcyclopropylmethyl]pyrrole-2 -carboxylate

Phosphorus oxychloride (2.15 g, 14 mmol) was added to a solution ofdimethylformamide (1.10 g, 15 mmol) in toluene (2 ml) and the mixturewas stirred at room temperature for 30 minutes. To this mixture wasadded a solution of methyl4,5-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrole-2-carboxylate(2.21 g, 10 mmol) in toluene (6 ml) and the mixture was heated at 80° C.for 10 hours. After the reaction was completed, the reaction mixture waspoured into water and neutralized with a saturated aqueous sodiumhydrogencarbonate solution. The organic layer was separated, washed witha saturated aqueous sodium chloride solution, dried over anhydrousmagnesium sulfate and then concentrated in vacuo. The residue waschromatographed on a column using ethyl acetate/hexane=10/1 as theeluant to afford the title compound (1.95 g, 78.2%) as a pale yellowoil.

Reference Example 37-(4-Fluorobenzyloxy)-2,3-dimethyl-1-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2.3-d]-pyridazine(a)7-(4-Fluorobenzyloxy)-1-[(E)-2-methylcyclopropylmethyl]-2,3-dimethylpyrrolo[2,3-d]pyridazine(racemate)

A reaction was carried out in a similar manner to that described inReference example 1 using (E)-2-methylcyclopropylmethyl bromide(racemate) instead of (1S,2S)-2-methylcyclopropylmethyl bromide toafford the desired compound (56%).

Mp: 120-122° C. Mass spectrum (CI, m/z): 340 (M⁺+1) 1H-NMR spectrumCDCl₃, δppm): 0.14 (dt; J=8 Hz, 5 Hz, 1H), 0.39 (dt; J=8 Hz, 5 Hz, 1H),0.59-0.65 (m, 1H), 0.76-0.85 (m, 1H), 0.89 (d; J=6 Hz, 3H), 2.26 (s,3H), 2.36 (s, 3H), 4.13 (dd; J=15 Hz, 7 Hz, 1H), 4.27 (dd; J=15 Hz, 6Hz, 1H), 5.63 (d; J=12 Hz, 1H), 5.68 (d; J=12 Hz, 1H), 7.05-7.12 (m,2H), 7.47-7.52 (m, 2H), 8.96(s, 1H).

(b)7-(4-Fluorobenzyloxy)-2,3-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d]pyridazine

7-(4-Fluorobenzyloxy)-1-[(E)-2-methylcyclopropylmethyl]-2,3-dimethylpyrrolo[2,3-d]pyridazine(racemate, 25 g) was chromatographed by high pressure liquidchromatography and recrystallized from ethyl acetate to afford the title[(S,S) form] compound (8.54 g) and the [(R,R) form] compound (7.60 g),which is the antipode of the [(S,S) form] compound.

Separation conditions;

Column: CHIRALCEL OJ, 50Φ×500 mm, Daicel Chemical Industries, Ltd.

Eluant: hexane/ethanol=90/10

Flow rate: 25 ml per minute

The title [(S,S) form] compound:

Mp: 114-115° C. Mass spectrum (CI, m/z): 340 (M⁺+1) 1H-NMR spectrum(CDCl₃, δppm): 0.14 (dt; J=8 Hz, 5 Hz, 1H), 0.39 (dt; J=8 Hz, 5 Hz, 1H),0.59-0.65 (m, 1H), 0.76-0.85 (m, 1H), 0.89 (d; J=6 Hz, 3H), 2.26 (s,3H),2.36 (s, 3H), 4.13 (dd; J=15 Hz, 7 Hz, 1H), 4.27 (dd; J=15 Hz, 6 Hz,1H), 5.63(d; J=12 Hz, 1H), 5.68 (d; J=12.2 Hz, 1H), 7.05-7.12 (m, 2H),7.47-7.52 (m, 2H ), 8.96(s, 1H). Optical rotation: [α]_(D) ²⁰=+19.0°(C=0.99, MeOH).

The antipode [(R,R) form] compound:

Mp: 114-115° C. Mass spectrum (CI, m/z): 340 (M⁺+1) NMR spectrum (CDCl₃,δppm): 0.15 (dt; J=8 Hz, 5 Hz, 1H), 0.39 (dt; J=8 Hz, 5 Hz, 1H),0.58-0.66 (m, 1H), 0.78-0.85 (m, 1H), 0.89 (d; J=6 Hz, 3H), 2.26 (s,3H), 2.37(s, 3H), 4.13 (dd; J=15 Hz, 7 Hz, 1H), 4.27 (dd; J=15 Hz, 6 Hz,1H), 5.63 (d; J=12 Hz, 1H), 5.68 (d; J=12 Hz, 1H), 7.06-7.11 (m, 2H),7.49-7.52 (m, 2H), 8.97 (s, 1H). Optical rotations: [α]_(D) ²⁰=18.8°(C=0.98, MeOH).

Test Example 1 Test on Activity of Proton•potassium-adenosineTriphosphatase (H⁺.K⁺-ATPase)

A microsomal fraction prepared in accordance with the method of Sachs,et al. [J. Bio. Chem., 251, 7690(1976)] by homogenizing a fresh gastricmucosal layer of swine and then subjecting the homogenate to densitygradient ultra centrifugation was employed as a protonpotassium-adenosine triphosphatase preparation. A solution (10 μl) of atest compound dissolved in dimethyl sulfoxide was added to 0.75 ml of a70 mM tris hydrochloric acid buffer (5 mM magnesium chloride, 20 mMpotassium chloride, pH=6.85) containing 30 to 80 μg/ml, in terms of theprotein concentration, of the enzyme preparation. The mixture wasincubated with 200 times/min of agitation at 37° C. for 45 minutes. Theenzymatic reaction was started by adding 0.25 ml of an 8 mM solution ofdisodium adenosine triphosphate. After this enzymatic reaction wascontinued for 20 minutes, 1 ml of a 10% trichloroacetic acid—activatedcharcoal (100 mg) solution was added to terminate the reaction. Thereaction mixture was centrifuged (at 4° C. and 3000 rpm for 15 minutes).Inorganic phosphoric acid formed by the hydrolysis of adenosinetriphosphate in the supernatant was subjected to colorimetry by themethod of Yoda, et al. [Biochem. Biophys. Res. Commun., 40, 880(1970)].The amount of inorganic phosphoric acid in a reaction mixture free frompotassium chloride was also measured. By subtracting this amount fromthe amount of inorganic phosphoric acid in the presence of potassiumchloride, protonpotassium-adenosine triphosphatase activity(H⁺.K⁺-ATPase) was determined. An inhibition ratio (%) was determinedfrom the active value of the control and the active value of the testcompound at each concentration, whereby a 50% inhibitory concentration(IC₅₀ μg/ml) against protonpotassium-adenosine triphosphatase wasdetermined. As a result, the compound of Example 2 had a 50% inhibitoryconcentration (IC₅₀) of 0.015 μg/ml, exhibiting excellent activity.

Test Example 2 Test for Inhibition on Gastric Acid Secretion in Rats

After a group of rats was fasted overnight, they were subjected tomidline abdominal incision and their pylorus was ligated underanesthesia with ether. The stomach and duodenum were returned to theiroriginal positions in the body, followed by closing at the abdominalincision part. A test compound (0.3 to 10 mg/ml) was suspended in anaqueous solution containing 0.5% of sodium carboxymethylcellulose and0.4% of Tween 80 (trade mark). The resulting suspension (1 ml/kg of bodyweight) was orally administered to the rats through a stomach tube. Fourhours after the ligation, the rats were sacrificed by inhalation of CO₂gas. They were subjected to abdominal incision to remove their stomach.The content of the stomach was collected in a glass-made graduatedcentrifuge tube. After centrifugation, the amount (ml) of thesupernatant and the amount (ml) of the precipitate were measured. Theprecipitate of the amount exceeding 0.5 ml was regarded as feces andexcluded from the data. The supernatant (100 μg) was poured into a testtube. Distilled water (4 ml) was added to the solution, and the solutionwas titrated to pH 7.0 with 0.01 N sodium hydroxide. A standard acidconcentration solution obtained by adding 4 ml of distilled water to 100μl of 0.1 N hydrochloric acid was titrated in a similar manner. Eachparameter was calculated in accordance with the following equations:

(1) Acid concentration of gastric juice (mEq/l)=A/B×100

A: amount (ml) of sodium hydroxide required for titration of 100 μl ofsupernatant

B: amount (ml) of sodium hydroxide required for titration of 100 μl of0.1 N hydrochloric acid

(2) Gastric acid output (AO, μEq/hr)=amount (ml) of supernatant ofgastric juice×acid concentration of gastric juice (mEq/l)/4

(3) Inhibition ratio (%)=(C−D)/C×100

C: AO (μEq/hr) of vehicle-administered group

D: AO (μEq/hr) of test-compound-administered group

A 50% inhibitory dose (ID₅₀) was determined from a dose-inhibition ratiocurve on which an inhibition ratio at each dose versus logarithmic dosewas drawn in accordance with the least squares. 95% confidence limit wasdetermined according to Fieller's equation. As the results, the compoundof Example 2 exhibited excellent activity, that is, an ID₅₀ less than 10mg/kg.

Test Example 3 Antibacterial Action Against Helicobacter Pylori

The antibacterial activity of the compound of the invention wasevaluated by using Helicobacter pylori strains 9470, 9472 and 9474 anddetermining MIC (Minimum Inhibitory Concentration) of the compound ofthe invention against Helicobacter pylori.

Helicobacter pylori was cultured by plating for 4 days. A medium wasprepared by dissolving Brain Heart Infusion Agar (product of DifcoLaboratories) in a prescribed amount of distilled water, sterilizing inan autoclave, adding equine blood (product of Nippon Seibutsu Zairyo) togive a concentration thereof of 7% and then solidifying the mixture.

Under microaerophilic conditions, Helicobacter pylori which had beencultured at 37° C. for 4 days was suspended in physiological saline togive its viable count of about 10⁸ CFU/ml. The suspension was thendiluted to 100 times and a portion (about 10 μl) of the dilutedsuspension was inoculated in a medium for measuring MIC. The mediumemployed for measuring MIC has the same composition as the preculturemedium. A compound of this invention was dissolved in dimethyl sulfoxide(DMSO) and two-fold serial dilutions were made with sterilized water.After mixing the solution and the medium in a ratio of 1:99, asolidified product in the Petri dish was employed as an MIC measuringmedium. In a similar manner to that employed for the preculture,Helicobacter pylori was cultured at 37° C. for 3 days undermicroaerophilic conditions. After completion of the culturing, growth ofthe bacteria in the inoculated portion was visually observed. Theminimum concentration of a compound of this invention at which nobacterial growth was observed was designated as MIC (μg/ml). Thecompound of Example 2 exhibited excellent antibacterial activity, thatis, an MIC less than 12.5 μg/ml.

Formulation Example 1 Tablets The compound of Example 2  30.0 mg Lactose144.0 mg Corn starch  25.0 mg Magnesium stearate  1.0 mg 200.0 mg

A tablet is prepared using the ingredients above. The components areblended and compressed by a tablet machine to form a tablet weighing 200mg. The tablet may be coated if necessary, for example, to form asugar-coated tablet.

The compounds of formula (I) or pharmaceutically acceptable saltsthereof of this invention exhibit potent gastric acid secretioninhibition activity, gastric mucous membrane protection activity andpotent antibacterial activity against Helicobacter pylori and they haveexcellent properties as medicaments. The compounds of formula (I) orpharmaceutically acceptable salts thereof are useful as a medicament,particularly for prevention or for therapeutic treatment for ulcerativediseases such as peptic ulcer, acute or chronic gastric ulcer,gastrisis, reflux esophagitis, gastroesophageal reflux disorder,dyspepsia, gastric hyperacidity or Zollinger-Ellison syndrome etc. andfor administration for prevention or for treatment of bacterialinfections arising from Helicobacter pylori.

What is claimed is:
 1. A pyrrolopyridazine compound having the followingformula or a pharmaceutically acceptable salt thereof:

wherein: R¹ is selected from the group consisting of C₂-C₆ alkenylgroups, halogeno C₂-C₆ alkenyl groups, C₃-C₇ cycloalkyl groups which maybe optionally substituted with a C₁-C₆ alkyl group and C₃-C₇cycloalkyl-C₁-C₆ alkyl groups which may be optionally substituted with aC₁-C₆ alkyl group; R² represents a C₁-C₆ alkyl group; R³ is selectedfrom the group consisting of hydroxymethyl groups, C₂-C₆ aliphaticacyloxymethyl groups, C₆-C₁₀ arylcarbonyloxymethyl groups which may beoptionally substituted with substituents selected from the groupconsisting of C₁-C₆ alkyl groups, C₁-C₆ alkoxy groups and halogen atoms,C₁-C₆ alkoxycarbonyloxymethyl groups, formyl groups, carboxyl groups,C₁-C₆ alkoxycarbonyl groups and C₆-C₁₀ aryloxycarbonyl groups which maybe optionally substituted with substituents selected from the groupconsisting of C₁-C₆ alkyl groups, C₁-C₆ alkoxy groups and halogen atoms;R⁴ represents a C₆-C₁₀ aryl group which may be optionally substitutedwith substituents selected from the group consisting of C₁-C₆ alkylgroups, halogeno C₁-C₆ alkyl groups, C₁-C₆ alkoxy groups, halogeno C₁-C₆alkoxy groups and halogen atoms; and A is selected from the groupconsisting of imino groups, oxygen atoms and sulfur atoms.
 2. Apyrrolopyridazine compound or a pharmaceutically acceptable salt thereofaccording to claim 1, wherein R¹ is selected from the group consistingof C₂-C₄ alkenyl groups, C₃-C₄ alkenyl groups substituted with fluoro orchloro, C₃-C₆ cycloalkyl groups which may be optionally substituted witha C₁-C₂ alkyl group and C₃-C₆ cycloalkyl-C₁-C₂ alkyl groups which may beoptionally substituted with a C₁-C₂ alkyl group.
 3. A pyrrolopyridazinecompound or a pharmaceutically acceptable salt thereof according toclaim 1, wherein R¹ is selected from the group consisting of C₃-C₄alkenyl groups, 3-chloro-2-propenyl groups, 3,3-difluoro-2-propenylgroups, 3,3-dichloro-2-propenyl groups, cyclopropyl groups,2-methylcyclopropyl groups, 2-ethylcyclopropyl groups, cyclobutylgroups, cyclopentyl groups, 2-methylcyclopentyl groups, cyclohexylgroups, 2-methylcyclohexyl groups, cyclopropylmethyl groups,2-methylcyclopropylmethyl groups, 2-ethylcyclopropylmethyl groups,cyclobutylmethyl groups, 2-methylcyclobutylmethyl groups,cyclopentylmethyl groups and 2-methylcyclohexylmethyl groups.
 4. Apyrrolopyridazine compound or a pharmaceutically acceptable salt thereofaccording to claim 1, wherein R¹ is selected from the group consistingof 2-propenyl groups, 2-butenyl groups, cyclopropyl groups,2-methylcyclopropyl groups, cyclopentyl groups, 2-methylcyclopentylgroups, cyclohexyl groups, 2-methylcyclohexyl groups, cyclopropylmethylgroups, 2-methylcyclopropylmethyl groups, cyclopentylmethyl groups and2-methylcyclohexylmethyl groups.
 5. A pyrrolopyridazine compound or apharmaceutically acceptable salt thereof according to claim 1, whereinR¹ is selected from the group consisting of 2-propenyl groups, 2-butenylgroups, cyclopropyl groups, 2-methylcyclopropyl groups,cyclopropylmethyl groups and 2-methylcyclopropylmethyl groups.
 6. Apyrrolopyridazine compound or a pharmaceutically acceptable salt thereofaccording to claim 1, wherein R¹ is selected from the group consistingof 2-butenyl groups, cyclopropylmethyl groups and2-methylcyclopropylmethyl groups.
 7. A pyrrolopyridazine compound or apharmaceutically acceptable salt thereof according to claim 1, whereinR² is a C₁-C₄ alkyl group.
 8. A pyrrolopyridazine compound or apharmaceutically acceptable salt thereof according to claim 1, whereinR² is a C₁-C₂ alkyl group.
 9. A pyrrolopyridazine compound or apharmaceutically acceptable salt thereof according to claim 1, whereinR² is a methyl group.
 10. A pyrrolopyridazine compound or apharmaceutically acceptable salt thereof according to claim 1, whereinR³ is selected from the group consisting of hydroxymethyl groups, C₂-C₆aliphatic acyloxymethyl groups, benzoyloxymethyl groups which may beoptionally substituted with a substituent selected from the groupconsisting of methyl groups, methoxy groups, fluoro and chloro, C₁-C₄alkoxycarbonyloxymethyl groups, formyl groups, carboxyl groups, C₁-C₄alkoxycarbonyl groups and phenyloxycarbonyl groups which may beoptionally substituted with a substituent selected from the groupconsisting of methyl groups, methoxy groups, fluoro and chloro.
 11. Apyrrolopyridazine compound or a pharmaceutically acceptable salt thereofaccording to claim 1, wherein R³ is selected from the group consistingof hydroxymethyl groups, C₂-C₆ aliphatic acyloxymethyl groups,benzoyloxymethyl groups, C₁-C₂ alkoxycarbonyloxymethyl groups, formylgroups, carboxyl groups, C₁-C₂ alkoxycarbonyl groups andphenyloxycarbonyl groups.
 12. A pyrrolopyridazine compound or apharmaceutically acceptable salt thereof according to claim 1, whereinR³ is selected from the group consisting of hydroxymethyl groups, C₂-C₄aliphatic acyloxymethyl groups, C₁-C₂ alkoxycarbonyloxymethyl groups,formyl groups, carboxyl groups and C₁-C₂ alkoxycarbonyl groups.
 13. Apyrrolopyridazine compound or a pharmaceutically acceptable salt thereofaccording to claim 1, wherein R³ is selected from the group consistingof hydroxymethyl groups, C₂-C₃ aliphatic acyloxymethyl groups, formylgroups and carboxyl groups.
 14. A pyrrolopyridazine compound or apharmaceutically acceptable salt thereof according to claim 1, whereinR³ is a hydroxymethyl group or an acetoxymethyl group.
 15. Apyrrolopyridazine compound or a pharmaceutically acceptable salt thereofaccording to claim 1, wherein R⁴ is a phenyl group which is substitutedwith 1 to 3 substituents selected from the group consisting of C₁-C₄alkyl groups, halogeno C₁-C₄ alkyl groups, C₁-C₄ alkoxy groups, halogenoC₁-C₄ alkoxy groups, fluoro, chloro and bromo.
 16. A pyrrolopyridazinecompound or a pharmaceutically acceptable salt thereof according toclaim 1, wherein R⁴ is a phenyl group which is substituted with 1 to 3substituents selected from the group consisting of a methyl group, atrifluoromethyl group, a methoxy group, a trifluoromethoxy groups, adifluoromethoxy group, fluoro, chloro and bromo.
 17. A pyrrolopyridazinecompound or a pharmaceutically acceptable salt thereof according toclaim 1, wherein R⁴ is a phenyl group which is substituted at theposition(s) selected from the group consisting of 2-, 4- and 6-positionof the phenyl group with 1 or 2 substituents selected from the groupconsisting of fluoro and chloro.
 18. A pyrrolopyridazine compound or apharmaceutically acceptable salt thereof according to claim 1, whereinR⁴ is a phenyl group which is substituted at the 4-position,2,4-positions or 2,6-positions of the phenyl group with 1 or 2substituents selected from the group consisting of fluoro and chloro.19. A pyrrolopyridazine compound or a pharmaceutically acceptable saltthereof according to claim 1, wherein A is an oxygen atom or a sulfuratom.
 20. A pyrrolopyridazine compound or a pharmaceutically acceptablesalt thereof according to claim 1, wherein A is an oxygen atom.
 21. Apyrrolopyridazine compound or a pharmaceutically acceptable salt thereofaccording to claim 1, wherein: R¹ is selected from the group consistingof C₂-C₄ alkenyl groups, C₃-C₄ alkenyl groups substituted with fluoro orchloro, C₃-C₆ cycloalkyl groups which may be optionally substituted witha C₁-C₂ alkyl group and C₃-C₆ cycloalkyl-C₁-C₂ alkyl groups which may beoptionally substituted with a C₁-C₂ alkyl group; R² is a C₁-C₄ alkylgroup; R³ is selected from the group consisting of hydroxymethyl groups,C₂-C₆ aliphatic acyloxymethyl groups, benzoyloxymethyl groups which maybe optionally substituted with a substituent selected from the groupconsisting of methyl groups, methoxy groups, fluoro and chloro, C₁-C₄alkoxycarbonyloxymethyl groups, formyl groups, carboxyl groups, C₁-C₄alkoxycarbonyl groups and phenyloxycarbonyl groups which may beoptionally substituted with a substituent selected from the groupconsisting of methyl groups, methoxy groups, fluoro and chloro; R⁴ is aphenyl group which is substituted with 1 to 3 substituents selected fromthe group consisting of C₁-C₄ alkyl, halogeno C₁-C₄ alkyl, C₁-C₄ alkoxy,halogeno-C₁-C₄ alkoxy, fluoro, chloro and bromo; and A is an oxygen atomor a sufur atom.
 22. A pyrrolopyridazine compound or a pharmaceuticallyacceptable salt thereof according to claim 1, wherein: R¹ is selectedfrom the group consisting of C₃-C₄ alkenyl groups, 3-chloro-2-propenylgroups, 3,3-difluoro-2-propenyl groups, 3,3-dichloro-2-propenyl groups,cyclopropyl groups, 2-methylcyclpropyl groups, 2-ethylcyclopropylgroups, cyclobutyl groups, cyclopentyl groups, 2-methylcyclopentylgroups, cyclohexyl groups, 2-methylcyclohexyl groups, cyclopropylmethylgroups, 2-methylcyclopropylmethyl groups, 2-ethylcyclopropylmethylgroups, cyclobutylmethyl groups, 2-methylcyclobutylmethyl groups,cyclopentylmethyl groups and 2-methylcyclohexylmethyl groups; R² is aC₁-C₄ alkyl group; R³ is selected from the group consisting ofhydroxymethyl groups, C₂-C₆ aliphatic acyloxymethyl groups,benzoyloxymethyl groups, C₁-C₂ alkoxycarbonyloxymethyl groups, formylgroups, carboxyl groups, C₁-C₂ alkoxycarbonyl groups andphenyloxycarbonyl groups; R⁴ is a phenyl group which is substituted with1 to 3 substituents selected from the group consisting of methyl groups,trifluoromethyl groups, methoxy groups, trifluoromethoxy groups,difluoromethoxy groups, fluoro, chloro and bromo; and A is an oxygenatom or a sulfur atom.
 23. A pyrrolopyridazine compound or apharmaceutically acceptable salt thereof according to claim 1, wherein:R¹ is selected from the group consisting of 2-propenyl groups, 2-butenylgroups, cyclopropyl groups, 2-methylcyclopropyl groups, cyclopentylgroups, 2-methylcyclopentyl groups, cyclohexyl groups,2-methylcyclohexyl groups, cyclopropylmethyl groups,2-methylcyclopropylmethyl groups, cyclopentylmethyl groups and2-methylcyclohexylmethyl groups; R² is a C₁-C₂ alkyl group; R³ isselected from the group consisting of hydroxymethyl groups, C₂-C₄aliphatic acyloxymethyl groups, C₁-C₂ alkoxycarbonyloxymethyl groups,formyl groups, carboxyl groups and C₁-C₂ alkoxycarbonyl groups; R⁴ is aphenyl group which is substituted at the position(s) selected from thegroup consisting of 2-, 4- and 6-position of the phenyl group with 1 or2 substituents selected from the group consisting of fluoro and chloro;and A is an oxygen atom.
 24. A pyrrolopyridazine compound or apharmaceutically acceptable salt thereof according to claim 1, wherein:R¹ is selected from the group consisting of 2-propenyl groups, 2-butenylgroups, cyclopropyl groups, 2-methylcyclopropyl groups,cyclopropylmethyl groups and 2-methylcyclopropylmethyl groups, R² is aC₁-C₂ alkyl group; R³ is selected from the group consisting ofhydroxymethyl groups, C₂-C₃ aliphatic acyloxymethyl groups, formylgroups and carboxyl groups; R⁴ is a phenyl group which is substituted atthe position(s) selected from the group consisting of 2-, 4- and6-position of the phenyl group with 1 or 2 substituents selected fromthe group consisting of fluoro and chloro; and A is an oxygen atom. 25.A pyrrolopyridazine compound or a pharmaceutically acceptable saltthereof according to claim 1, wherein: R¹ is selected from the groupconsisting of 2-butenyl groups, cyclopropylmethyl groups and2-methylcyclopropylmethyl groups; R² is a methyl group; R³ is ahydroxymethyl group or an acetoxymethyl group; R⁴ is a phenyl groupwhich is substituted at the 4-position, 2,4-positions or, 2,6-positionsof the phenyl group with 1 or 2 substituents selected from the groupconsisting of fluoro and chloro; and A is an oxygen atom.
 26. Apyrrolopyridazine compound selected from the following group or apharmaceutically acceptable salt thereof:1-(2-butenyl)-7-(4-fluorobenzyloxy)-3-hydroxymethyl-2-methylpyrrolo[2,3-d]pyridazine,7-(4-fluorobenzyloxy)-3-hydroxymethyl-2-methyl-1-(2-methylcyclopropylmethyl)pyrrolo[2,3-d]pyridazine,1-(2-butenyl)-7-(2,4-difluorobenzyloxy)-3-hydroxymethyl-2-methylpyrrolo[2,3-d]pyridazine,7-(2,4-difluorobenzyloxy)-3-hydroxymethyl-2-methyl-1-(2-methylcyclopropylmethyl)pyrrolo[2,3-d]pyridazine,3-acetoxymethyl-7-(4-fluorobenzyloxy)-2-methyl-1-(2-methylcyclopropylmethyl)pyrrolo[2,3-d]pyridazine,and3-acetoxymethyl-7-(2,4-difluorobenzyloxy)-2-methyl-1-(2-methylcyclopropylmethyl)pyrrolo[2,3-d]pyridazine.27. A pyrrolopyridazine compound according to claim
 26. 28. Apyrrolopyridazine compound or a pharmaceutically acceptable salt thereofaccording to claim 1, which is3-acetoxymethyl-7-(4-fluorobenzyloxy)-2-methyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d]pyridazineor a pharmaceutically acceptable salt thereof.
 29. A pyrrolopyridazinecompound according to claim
 28. 30. A pyrrolopyridazine compound or apharmaceutically acceptable salt thereof according to claim 1, which is7-(4-fluorobenzyloxy)-3-hydroxymethyl-2-methyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d]pyridazine or apharmaceutically acceptable salt thereof.
 31. A pyrrolopyridazinecompound according to claim
 30. 32. A pyrrolopyridazine compound or apharmaceutically acceptable salt thereof according to claim 1, which is7-(4-fluorobenzyloxy)-3-formyl-2-methyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d]pyridazineor a pharmaceutically acceptable salt thereof.
 33. A pyrrolopyridazinecompound according to claim
 32. 34. A pyrrolopyridazine compound or apharmaceutically acceptable salt thereof according to claim 1, which is3-carboxy-7-(4-fluorobenzyloxy)-2-methyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d]pyridazineor a pharmaceutically acceptable salt thereof.
 35. A pyrrolopyridazinecompound according to claim
 34. 36. A pharmaceutical compositioncomprising (i) a pharmacologically acceptable carrier and (ii) apyrrolopyridazine compound or a pharmaceutically acceptable salt thereofaccording to any one of claims 1 to
 35. 37. A method for the prophylaxisor treatment of an ulcerative disease which comprises administering to awarm-blooded animal in need thereof a pharmaceutically effective amountof a pyrrolopyridazine compound or a pharmaceutically acceptable saltthereof according to anyone of claims 1 to
 35. 38. A method for theprophylaxis or treatment of an ulcerative disease which comprisesadministering to a human in need thereof a pharmaceutically effectiveamount of a pyrrolopyridazine compound or a pharmaceutically acceptablesalt thereof according to anyone of claims 1 to
 35. 39. A method for thetreatment of a Helicobacter pylori infection in a warm-blooded animalwhich comprises administering to said warm-blooded animal apharmaceutically effective amount of a pyrrolopyridazine compound or apharmaceutically acceptable salt thereof according to anyone of claims 1to
 20. 40. A method for the treatment of a Helicobacter pylori infectionin a human which comprises administering to said human apharmaceutically effective amount of a pyrrolopyridazine compound or apharmaceutically acceptable salt thereof according to anyone of claims21 to 35.